Chemical compounds

ABSTRACT

The invention provides compounds formula I, their preparation, and their use as pharmaceutically active immuno-suppressive agents for the treatment of autoimmune disorders, organ transplant rejection, disorders associated with an activated immune system, as well as other disorders modulated by lymphopenia or SIP receptors.

RELATED APPLICATIONS

This application is related and claims priority to U.S. provisionalapplication Ser. No. 60/821,101, filed Aug. 1, 2006, U.S. provisionalapplication Ser. No. 60/827,919, filed Oct. 3, 2006, U.S. provisionalapplication Ser. No. 60/896,431, filed Mar. 22, 2007 and U.S.provisional application Ser. No. 60/959,291, filed Jul. 12, 2007, theentire contents of each of which are incorporated herein by thisreference.

BACKGROUND OF THE INVENTION

The sphingosine-1-phosphate (S1P) receptors 1-5 constitute a family ofseven transmembrane G-protein coupled receptors. These receptors,referred to as S1P-1 to S1P-5, are activated via binding bysphingosine-1-phosphate, which is produced by the sphingosinekinase-catalyzed phosphorylation of sphingosine. S1P receptors are cellsurface receptors involved in a variety of cellular processes, includingcell proliferation and differentiation, cell survival, cell invasion,lymphocyte trafficking, and cell migration. Sphingosine-1-phosphate isfound in plasma and a variety of other tissues, and exerts autocrine andparacrine effects, including regulating the secretion of growth factors.

Administration of S1P to an animal results in sequestration oflymphocytes into the lymph nodes and Peyers patches without causinglymphocyte depletion. This activity, which is of potential utility intreating diseases or conditions associated with inappropriate immuneresponse, including transplant rejection, autoimmune diseases, as wellas other disorders modulated by lymphocyte trafficking, is believed toproceed via activation of the S1P-1 receptor. Administration of S1P invivo has been shown to cause hypotension and bradycardia, which arebelieved to be due to signaling through one or more of the other S1Preceptors, i.e. S1P-2 to S1P-5. Accordingly, there is a need forcompounds which are potent and selective agonists of the S1P-1 receptor.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention. In some aspects,the present invention is directed to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, or dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, haloalkyl, —CF₃, aryl, —CN, —OH, or—O-alkyl;

A is (C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, eachof which may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;

X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H⁻ or (C₁-C₆)alkyl;

R′ and R″ are each independently hydrogen, halogen, alkyl optionallysubstituted on carbon with halogen, alkyl, or taken together with thecarbon to which they are attached form C═O or a 3, 4, 5, or 6-memberedring, optionally containing 1 or 2 heteroatoms selected from ONH,N-alkyl, SO, or SO₂, any of which may be optionally substituted oncarbon with alkyl or halogen

R₂ is cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroalykl, —O-alkyl, —O-aryl, —O-heteroaryl, aralkoxy,heteroaralkoxy, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, and dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, OH, or —O-alkyl;

R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₇alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, alkyl, alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, CO₂-alkyl,alkylene-OC(O)alkyl, cycloalkyl, heterocyclo, —C(O)-alkyl, —C(O)-aryl,C(O)-aralkyl, —C(O)-Oalkyl, —C(O)-Oaryl, —C(O)-Oaralkyl, alkylene-amino,alkylene-alkylamino, and alkylene-dialkylamino, any of which may beoptionally substituted on carbon with halogen, alkyl, hydroxyl, CO₂H,CO₂alkyl or alkoxy; or

R₅ and R₆, together with the nitrogen to which they are attached, mayform a 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy;

R₇ is selected from the group consisting of —OH, —O-alkyl, alkylene-OH,—CO₂H, alkylene-CO₂H, —C(O)O-alkyl, -alkylene-CO₂-alkyl, —C(O)O-aryl,—CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl, —CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2),—OPO₃R_(p1)R_(p2), —CH₂PO₃R_(p1)R_(p2), —OPO₂(S)R_(p1)R_(p2), and—C(Z′)(Z″)PO₃R_(p1)R_(p2), any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein

Z′ is hydroxyl or halogen;

Z″ is H or halogen;

R_(p1), and R_(p2) are each independently hydrogen, C₁-C₆-alkyl, aryl,or one of the following groups:

and

Y is heterocyclo or heteroaryl.

In some embodiments, R₂ is alkyl substituted with 1, 2 or 3 halo groups.In some embodiments, R₂ is trifluoromethyl.

In other aspects, the present invention is directed to a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, or dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, haloalkyl, —CF₃, —CN, —OH, or—O-alkyl;

A is (C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, eachof which may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;

X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl;

R′ and R″ are each independently hydrogen, halogen, alkyl optionallysubstituted on carbon with halogen, alkyl, or taken together with thecarbon to which they are attached form C═O or a 3, 4, 5, or 6-memberedring, optionally containing 1 or 2 heteroatoms selected from ONH,N-alkyl, SO, or SO₂, any of which may be optionally substituted oncarbon with alkyl or halogen

R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, alkyl, alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, CO₂-alkyl,alkylene-OC(O)alkyl, cycloalkyl, heterocyclo, —C(O)-alkyl, —C(O)-aryl,C(O)-aralkyl, —C(O)-Oalkyl, —C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino,alkylene-alkylamino, and alkylene-dialkylamino, any of which may beoptionally substituted on carbon with halogen, alkyl, hydroxyl, CO₂H,CO₂alkyl or alkoxy; or

R₅ and R₆, together with the nitrogen to which they are attached, mayform a 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy;

R₇ is selected from the group consisting of —OH, —O-alkyl, -alkylene-OH,—CO₂H, -alkylene-CO₂H, —C(O)O-alkyl, -alkylene-CO₂-alkyl, —C(O)O-aryl,—CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl, —CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2),—OPO₃R_(p1)R_(p2), —CH₂PO₃R_(p1)R_(p2), —OPO₂(S)R_(p1)R_(p2), and—C(Z′)(Z″)PO₃R_(p1)R_(p2), any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein

Z′ is hydroxyl or halogen;

Z″ is H or halogen;

R_(p1) and R_(p2) are each independently hydrogen, C₁-C₆-alkyl, aryl, orone of the following groups:

and

Y is heterocyclo or heteroaryl.

In some embodiments, compounds of the present invention includecompounds listed in the following table:

as well as pharmaceutically acceptable salts, phosphate derivatives,phosphate mimics, or phosphate precursor analogs thereof.

In some aspects, the present invention is directed to a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, or dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, haloalkyl, —CF₃, —CN, —OH, or—O-alkyl;

A is (C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, eachof which may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;

X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl;

R′ and R″ are each independently hydrogen, halogen, alkyl optionallysubstituted on carbon with halogen, alkyl, or taken together with thecarbon to which they are attached form C═O or a 3, 4, 5, or 6-memberedring, optionally containing 1 or 2 heteroatoms selected from ONH,N-alkyl, SO, or SO₂, any of which may be optionally substituted oncarbon with alkyl or halogen R₃ is absent, hydrogen, halogen, cyano,alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl,heteroalykl, —O-alkyl, —O-aryl, —O-heteroaryl, aralkoxy, heteroaralkoxy,—S-alkyl, alkylene-O-alkyl, alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂,alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino,alkylene-CO-dialkylamino, alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl—CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂, —CO-alkylamino,—CO-dialkylamino, amino, alkylamino, and dialkylamino, any of which maybe optionally substituted on carbon with 1, 2, or 3 groups selected fromhalo, alkyl, OH, or —O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, alkyl, alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, CO₂-alkyl,alkylene-OC(O)alkyl, cycloalkyl, heterocyclo, —C(O)-alkyl, —C(O)-aryl,C(O)-aralkyl, —C(O)-Oalkyl, —C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino,alkylene-alkylamino, and alkylene-dialkylamino, any of which may beoptionally substituted on carbon with halogen, alkyl, hydroxyl, CO₂H,CO₂alkyl or alkoxy; or

R₅ and R₆, together with the nitrogen to which they are attached, mayform a 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy;

R₈ is hydrogen, alkyl or aryl; and

n is 0, 1, or 2.

In some embodiments, compounds of the present invention includecompounds listed in the following table:

wherein n for each compound is 0, 1 or 2, as well as pharmaceuticallyacceptable salts, phosphate derivatives, phosphate mimics, or phosphateprecursor analogs thereof.

In some aspects, the present invention is directed to compound selectedfrom:

-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol;-   2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propane-1,3-diol;-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(decyloxy)-3(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(3-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(S-(4-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-(3-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-((4-phenyl-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(7-phenylheptyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-phenethoxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(3-phenylpropoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzofuran-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzo[b]thiophen-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzo[d][1,3]dioxol-5-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(3-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (2S)-2-Amino-2-(5-(4-(3,7-dimethyloctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-propylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-butylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-ethylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(7,7,8,8,8-pentafluorooctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(2-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(3-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(4-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-(2-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(3-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-(4-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-(3,4-difluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(2,4,5-trifluorophenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(3-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(4-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(octylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(octylsulfonyl)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol;-   (R)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-1-ol;-   (S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)    thiazol-2-yl)propan-1-ol;    and pharmaceutically acceptable salts, phosphate derivatives,    phosphate mimics, and phosphate precursor analogs thereof.

In some aspects, the present invention is directed to a compound whichis(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-olor a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or phosphate precursor analog thereof._In other aspects, thepresent invention is directed to a compound which is(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention is directed to a compound whichis(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-olor a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or a phosphate precursor analog thereof. In other aspects, thepresent invention is directed to a compound which is(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention is directed to a method oftreating a sphingosine 1-phosphate associated disorder in a subject inneed thereof comprising administering to the subject a therapeuticallysafe and effective amount of a compound of any of formulas I, II or III,or a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or phosphate precursor analog thereof, such that the sphingosine1-phosphate associated disorder is treated.

In some aspects, the present invention is directed to a method oftreating an autoimmune disorder comprising administering to a subject inneed thereof a pharmaceutically acceptable amount of a compound of anyof formulas I, II or III, such that the autoimmune disorder is treated.

In some aspects, the present invention is directed to a method treatingtransplant rejection comprising administering to a subject in needthereof a pharmaceutically acceptable amount of a compound of any offormulas I, II or III, such that the transplant rejection is treated.

In some aspects, the present invention is directed to a compound of anyof formulas I, II or III for use as a therapeutic substance.

In some aspects, the present invention is directed to a compound of anyof formulas I, II or III for use in the treatment of sphingosineassociated disorders. In some aspects, the present invention is directedto a compound of any of formulas I, II or III for use in the treatmentof multiple sclerosis.

In some aspects, the present invention is directed to a compound of anyof formulas I, II or III for use in the manufacture of a medicament foruse in the treatment of sphingosine associated disorders. In someaspects, the present invention is directed to a compound of any offormulas I, II or III for use in the manufacture of a medicament for thetreatment of multiple sclerosis.

In some aspects, the present invention is directed to a pharmaceuticalcomposition comprising a compound of any of formulas I, II or III and apharmaceutically acceptable carrier.

In some aspects, the present invention is directed to a process formaking any of the compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are used, unless otherwise described.

“Halogen” or “halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “hydrocarbon” used alone or as a suffix or prefix, refers toany structure comprising only carbon and hydrogen atoms up to 14 carbonatoms.

The term “hydrocarbon radical” or “hydrocarbyl” used alone or as asuffix or prefix, refers to any structure as a result of removing one ormore hydrogens from a hydrocarbon.

The term “alkyl” used alone or as a suffix or prefix, refers tomonovalent straight or branched chain hydrocarbon radicals comprising 1to about 12 carbon atoms.

The term “alkylene” used alone or as suffix or prefix, refers todivalent straight or branched chain hydrocarbon radicals comprising 1 toabout 12 carbon atoms, which serves to links two structures together.

The term “cycloalkyl” used alone or as suffix or prefix, refers to asaturated or partially unsaturated monovalent ring-containinghydrocarbon radical comprising at least 3 up to about 12 carbon atoms.

The term “aryl” used alone or as suffix or prefix, refers to amonovalent hydrocarbon radical having one or more polyunsaturated carbonrings having aromatic character, and comprising 5 up to about 14 carbonatoms.

The term “heterocycle” used alone or as a suffix or prefix, refers to aring-containing structure or molecule having one or more multivalentheteroatoms, independently selected from N, O and S, as a part of thering structure and including at least 3 and up to about 20 atoms in thering(s). Heterocycle may be saturated or unsaturated, containing one ormore double bonds, and heterocycle may contain more than one ring. Whena heterocycle contains more than one ring, the rings may be fused orunfused. Fused rings generally refer to at least two rings share twoatoms therebetween. Heterocycle may have aromatic character or may nothave aromatic character.

The terms “heterocyclic group”, “heterocyclic moiety”, “heterocyclic”,or “heterocyclo” used alone or as a suffix or prefix, refers to aradical derived from a heterocycle by removing one or more hydrogenstherefrom.

The term “heterocyclyl” used alone or as a suffix or prefix, refers amonovalent radical derived from a heterocycle by removing one hydrogentherefrom.

The term “heteroaryl” used alone or as a suffix or prefix, refers to aheterocyclyl having aromatic character.

Heterocycle includes, for example, monocyclic heterocycles such as:aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolane2,3-dihydrofuran, 2,5-dihydrofuran tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydro-pyridine, piperazine, morpholine,thiomorpholine, pyran, thiopyran, 2,3-dihydropyran, tetrahydropyran,1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane, dioxane, homopiperidine,2,3,4,7-tetrahydro-1H-azepine homopiperazine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

In addition, heterocycle includes aromatic heterocycles (heteroarylgroups), for example, pyridine, pyrazine, pyrimidine, pyridazine,thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazole,pyrazole, isothiazole, isoxazole, 1,2,3-triazole, tetrazole,1,2,3-thiadiazole, 1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole,1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4-thiadiazole, and1,3,4-oxadiazole.

Additionally, heterocycle encompass polycyclic heterocycles, forexample, indole, indoline, isoindoline, quinoline, tetrahydroquinoline,isoquinoline, tetrahydroisoquinoline, 1,4-benzodioxan, coumarin,dihydrocoumarin, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran,chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene,indolizine, isoindole, indazole, purine, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine,perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine,1,2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole,benzimidazole, benztriazole, thioxanthine, carbazole, carboline,acridine, pyrolizidine, and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycleincludes polycyclic heterocycles wherein the ring fusion between two ormore rings includes more than one bond common to both rings and morethan two atoms common to both rings. Examples of such bridgedheterocycles include quinuclidine, diazabicyclo[2.2.1]heptane and7-oxabicyclo[2.2.1]heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyls, such as:aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl,dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl,tetrahydrofuranyl, thiophanyl, piperidinyl,1,2,3,6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl,pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl,1,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl,homopiperidinyl, 2,3,4,7-tetrahydro-1H-azepinyl, homopiperazinyl,1,3-dioxepanyl, 4,7-dihydro-1,3-dioxepinyl, and hexamethylene oxidyl.

In addition, heterocyclyl includes aromatic heterocyclyls or heteroaryl,for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl,furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.

Additionally, heterocyclyl encompasses polycyclic heterocyclyls(including both aromatic or non-aromatic), for example, indolyl,indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, 1,4-benzodioxanyl, coumarinyl,dihydrocoumarinyl, benzofuranyl, 2,3-dihydrobenzofuranyl,isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl,phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl,purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,cinnolinyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl,benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl,pyrolizidinyl, and quinolizidinyl.

In addition to the polycyclic heterocyclyls described above,heterocyclyl includes polycyclic heterocyclyls wherein the ring fusionbetween two or more rings includes more than one bond common to bothrings and more than two atoms common to both rings. Examples of suchbridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl;and 7-oxabicyclo[2.2.1]heptyl.

The term “six-membered” used as prefix refers to a group having a ringthat contains six ring atoms.

The term “five-membered” used as prefix refers to a group having a ringthat contains five ring atoms.

A five-membered heteroaryl ring is a heteroaryl with a ring having fivering atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S. Exemplary five-membered ring heteroaryls are thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and1,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having sixring atoms wherein 1, 2 or 3 ring atoms are independently selected fromN, O and S. Exemplary six-membered ring heteroaryls are pyridyl,pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “heteroaralkyl” refers to an alkyl group substituted with anheteroaryl group.

Unless otherwise specified, the term “substituted”, when used as aprefix, refers to a structure, molecule or group, wherein one or morehydrogens are replaced with one or more alkyl groups, or one or morechemical groups containing one or more heteroatoms selected from N, O,S, F, Cl, Br, I, and P. Exemplary chemical groups containing one or moreheteroatoms include heterocyclyl, —NO₂, —O-alkyl, halo, —CF₃, —CO₂H,—CO₂R, —NH₂, —SH, —NHR, —NR₂, —SR, —SO₃H, —SO₂R, —S(O)R, —CN, —OH,—C(O)NR₂, —NRC(O)R, oxo (═O), imino (═NR), thio (═S), and oximino(═N—OR), wherein each “R” is alkyl as defined above. For example,substituted phenyl may refer to nitrophenyl, pyridylphenyl,methoxyphenyl, chlorophenyl, aminophenyl, an so on, wherein the nitro,pyridyl, methoxy, chloro, and amino groups may replace any suitablehydrogen on the phenyl ring. It will be understood that “substitution”or “substituted with” includes the implicit proviso that suchsubstitution is in accordance with the permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

The term “alkoxy” used alone or as a suffix or prefix, refers toradicals of the general —O-alkyl, Exemplary alkoxy groups includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy,cyclopropylmethoxy, allyloxy, and propargyloxy.

The term “amine” or “amino” used alone or as a suffix or prefix, refers—NH₂.

The term “alkylamino” used alone or as a suffix or prefix, refers—NH(alkyl). The term “dialkylamino” used alone or as a suffix or prefix,refers —NH(alkyl)₂.

“Acyl” used alone, as a prefix or suffix, means —C(O)—R, wherein Rhydrogen, hydroxyl, amino, alkylamino, dialkylamino, or alkoxy, any ofwhich may be substituted as provided by the definition of “substituted”given above. Acyl groups include, for example, acetyl, propionyl,benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.

Some of the compounds in the present invention may exist asstereoisomers, including enantiomers, diastereomers, and geometricisomers. All of these forms, including (R), (S), epimers, diastereomers,cis, trans, syn, anti, solvates (including hydrates), tautomers, andmixtures thereof, are contemplated in the compounds of the presentinvention.

The invention also relates to salts of the compounds of the inventionand, in particular, to pharmaceutically acceptable salts. A“pharmaceutically acceptable salt” is a salt that retains the desiredbiological activity of the parent compound and does not impart anyundesired toxicological effects. The salts can be, for example, saltswith a suitable acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and the like; acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, benzoic acid,pamoic acid, alginic acid, methanesulfonic acid, naphthalenesulfonicacid, and the like. Also included are salts of cations such as ammonium,sodium, potassium, lithium, zinc, copper, barium, bismuth, calcium, andthe like; or organic cations such as tetralkylammonium andtrialkylammonium cations. Combinations of the above salts are alsouseful. Salts of other acids and/or cations are also included, such assalts with trifluoroacetic acid, chloroacetic acid, and trichloroaceticacid. The invention also includes different crystal forms, hydrates, andsolvates of the compounds of the invention.

The terms “phosphate precursor” and “phosphate precursor analog,” asused herein, refer to substituent moieties in invention compounds thatmay be directly phosphorylated in vivo, or which may be cleaved in vivoto reveal a moiety that may then be phosphorylated in vivo. In certainembodiments, the phosphate precursor may be L₁-O—H or L₁-O-L₂, whereinL₁ is a linking moiety and L₂ is a labile moiety. Exemplary embodimentsof the phosphate precursor, include but are not limited to -alkyl-OH,-halo-alkyl-OH, alkoxy-OH, -alkyl-OCOR^(a), -halo-alkyl-OCOR^(a),-alkoxy-OCOR^(a), -alkyl-OC(O)NR^(a)R^(b),-halo-alkyl-OC(O)NHR^(a)R^(b), -alkoxy-OC(O)NR^(a)R^(b),—(CH₂)_(q)CO₂R^(c), and —(CH₂)_(n)CH₂═CHC(O)OR^(c), wherein

q is an integer between 0 and 4;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, straight chain or branched C₁-C₆-alkyl, all of which may beoptionally substituted with OH, halogen, straight chain or branchedC₁-C₆-alkoxy, straight chain or branched halo-C₁-C₆-alkyl, straightchain or branched halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,hydroxyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, substituted or unsubstitutedC₃-C₁₀ carbocyclic rings, and substituted or unsubstituted C₃-C₁₀heterocyclic rings, which may contain one or more heteroatoms and may besaturated or unsaturated; and

R^(c) is selected from the group consisting of hydrogen, straight chainor branched C₁-C₆-alkyl, straight chain or branched halo-C₁-C₆-alkyl,substituted or unsubstituted aryl group, or one of the following groups.

The “linking moiety,” may contain 1-8 atoms or may be a bond, and servesas the connection point through which the phosphate mimic, phosphatederivative, or phosphate precursor substituent moieties are linked tothe remaining structure of the compounds of the invention. In certainembodiments, the linking moiety may include, but is not limited to,substituted or unsubstituted alkyl (e.g., methylene chains), substitutedor unsubstituted alkenyl (e.g., n-alkenes), substituted or unsubstitutedalkynyl, substituted or unsubstituted halo-alkyl, substituted orunsubstituted alkoxy, and substituted or unsubstituted halo-alkoxy. Inspecific embodiments, the linking moiety may be carbonyl derivatized.

The language “labile moiety” refers to a moiety that is subject tocleavage, for instance, by hydrolysis or enzymatic degradation. Incertain embodiments, the labile moiety is an ester moiety, which mayresult in a carboxylate or hydroxyl derivative, depending on theorientation of the ester functionality in the molecule prior tocleavage.

The term “phosphate derivative” refers to substituent moieties ininvention compounds that contain a phosphate or phosphate ester group.When a compound of the invention containing a phosphate derivative isadministered to a subject, the compound may act as is in vivo or thephosphate derivative (within the compound) may be cleaved and thenre-phosphorylated in vivo leading to an active compound. In certainembodiments, the phosphate derivative may be selected from the groupconsisting of —(CH₂)_(q)OPO₂R^(d)R^(e), —(CH₂)_(q)OPO₃R_(d)R^(e), and—(CH₂)_(q)OPO₂(S)R^(d)R^(e), wherein

q is an integer between 0 and 4; and

R^(d) and R^(e) are each independently selected from the groupconsisting of hydrogen, straight chain or branched C₁-C₆-alkyl, straightchain or branched halo-C₁-C₆-alkyl, substituted or unsubstituted arylgroup, and a prodrug derivatizing moiety (PDM).

The term “phosphate mimic” refers to substituent moieties in inventioncompounds in which a phosphate substrate has been replaced with anon-hydrolyzable functional group, resulting in a moiety that mimics thebiological function of a phosphate or phosphate ester moiety. In certainembodiments, the phosphate mimic is -L₁-Z₂, wherein L₁ is a linkingmoiety and Z₂ is a non-hydrolyzable moiety covalently bonded, to L₁. Incertain embodiments, the phosphate mimic is selected from the groupconsisting of —(CH₂)_(q)CH₂PO₃R^(d)R^(e), and—(CH₂)_(q)C(Y₁)(Y₂)PO₃R^(d)R^(e), wherein

q is an integer between 0 and 4;

Y₁ and Y₂ are independently selected from the group consisting ofhydrogen, straight chain or branched C₁-C₆-alkyl, all of which may beoptionally substituted with OH, halogen, straight chain or branchedC₁-C₆-alkoxy, straight chain or branched halo-C₁-C₆-alkyl, straightchain or branched halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,hydroxyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, substituted or unsubstitutedC₃-C₁₀ carbocyclic rings, and substituted or unsubstituted C₃-C₁₀heterocyclic rings, which may contain one or more heteroatoms and may besaturated or unsaturated; and

R^(d) and R^(e) are each independently selected from the groupconsisting of hydrogen, straight chain or branched C₁-C₆-alkyl, straightchain or branched halo-C₁-C₆-alkyl, substituted or unsubstituted arylgroup, and a prodrug derivatizing moiety (PDM).

The language “non-hydrolyzable moiety” is art-recognized, and refers tomoieties containing bonds, such as carbon-phosphorous bonds, that arenot hydrolyzable in vivo.

Compounds of the Invention

In some aspects, the present invention is directed to a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, or dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, haloalkyl, —CF₃, aryl, —CN, —OH, or—O-alkyl;

A is (C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, eachof which may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;

X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl;

R′ and R″ are each independently hydrogen, halogen, alkyl optionallysubstituted on carbon with halogen, alkyl, or taken together with thecarbon to which they are attached form C═O or a 3, 4, 5, or 6-memberedring, optionally containing 1 or 2 heteroatoms selected from ONH,N-alkyl, SO, or SO₂, any of which may be optionally substituted oncarbon with alkyl or halogen R₂ is cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, alkyl, alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, CO₂-alkyl,alkylene-OC(O)alkyl, cycloalkyl, heterocyclo, —C(O)-alkyl, —C(O)-aryl,C(O)-aralkyl, —C(O)-Oalkyl, —C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino,alkylene-alkylamino, and alkylene-dialkylamino, any of which may beoptionally substituted on carbon with halogen, alkyl, hydroxyl, CO₂H,CO₂alkyl or alkoxy; or

R₅ and R₆, together with the nitrogen to which they are attached, mayform a 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy;

R₇ is selected from the group consisting of —OH, —O-alkyl, alkylene-OH,—CO₂H, alkylene-CO₂H, —C(O)O-alkyl, -alkylene-CO₂-alkyl, —C(O)O-aryl,—CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl, —CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2),—OPO₃R_(p1)R_(p2), —CH₂PO₃R_(p1)R_(p2), —OPO₂(S)R_(p1)R_(p2), and—C(Z′)(Z″)PO₃R_(p1)R_(p2), any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein

Z′ is hydroxyl or halogen;

Z″ is H or halogen;

R_(p1) and R_(p2) are each independently hydrogen, C₁-C₆-alkyl, aryl, orone of the following groups:

and

Y is heterocyclo or heteroaryl.

In some embodiments, R₁ is aryl or heteroaryl, optionally substitutedwith 1, 2, or 3 groups selected from halo, alkyl, haloalkyl, -aryl,—CF₃, —CN, —OH, or —O-alkyl. In some embodiments, R₁ is aryl, e.g.,phenyl, optionally substituted with 1 or 2 groups selected from —CF₃,—CN, —OMe, —Cl or —F. In some embodiments, R₁ is heteroaryl, e.g.,thiophene or benzothiophene, optionally substituted with 1 or 2 groupsselected from phenyl, —CF₃, —CN, —OMe, —Cl or —F. In some embodiments,R₁ is hydrogen. In other embodiments, R₁ is phenyl. In some embodiments,R₁ is pyridyl. In other embodiments, R₁ is thiophenyl. In still otherembodiments, R₁ is cyclohexyl. In some embodiments, R₁ is cyclopentyl.

In some embodiments, A is a C₁-C₁₀ alkylene. In some embodiments, A is abranched C₁-C₁₀ alkylene. In other embodiments, A is n-octyl. In otherembodiments, A is n-heptyl. In other embodiments, A is n-hexyl. In someembodiments, A is a C₁-C₅ alkylene. In some embodiments, A is n-pentyl.In other embodiments, A is n-butyl. In still other embodiments, A isn-propyl. In other embodiments, A is ethyl. In still other embodiments,A is methyl.

In some embodiments, X₁ is O. In other embodiments, X₁ is S. In stillother embodiments, X₁ is SO₂. In some embodiments, X₁ is CH₂. In otherembodiments, X₁ is C═O. In still other embodiments, CH₂O, wherein eitherthe oxygen or the carbon may be attached to

In some embodiments, R′ is hydrogen. In other embodiments, R′ is methyl.In some embodiments, R″ is hydrogen. In other embodiments, R′ is methyl.In some embodiments, R′ and R″ taken together with the carbon to whichthey are attached, is C═O, with the provision that only one of X₁ or R′and R″ taken together with the carbon may form C═O.

The compounds of the present invention include a selectivity enhancingmoiety. The term “selectivity enhancing moiety (SEM)” is defined in U.S.application Ser. No. 11/349,069 filed on Feb. 6, 2006 which is assignedto the assignee of the present application, the contents of which areincorporated herein by reference, refers to one or more moieties thatprovide an enhancement in the selectivity of the compound to which theyare attached for the S1P-1 receptor, as compared to the compound notcontaining the moiety or moieties. The SEM confers selectivity to thecompound to which it is attached for the S1P-1 receptor as compared to,for example, the S1P-2 to S1P-5 receptors. The enhancement conferred toa compound by the SEM may be measured by, for example, determining thebinding specificity of a compound for the S1P-1 receptor and one or moreof the other S1P receptors wherein enhancement conferred to a compoundby the SEM may be in the form of increased potency. In some embodiments,at least one of R₂ and/or R₃ is an SEM. In some embodiments, the SEM isa halo-substituted alkyl group such as CF₃, CF₂CF₃, CF₂CF₂CF₃, CFHCF₃,CH₂CF₃, CH₂CH₂CF₃, CHCl₂, or CH₂Cl.

In certain embodiments, the SEM may possess a selectivity enhancingorientation (SEQ). The term “selectivity enhancing orientation” or“SEQ,” is defined in U.S. application Ser. No. 11/349,069 filed on Feb.6, 2006 which is assigned to the assignee of the present application,the contents of which are incorporated herein by reference and as usedherein refers to the relative selectivity enhancement of a compoundbased on the orientation of the SEM as well as the additionalsubstitutents on the ring, either alone or in combination with eachother. In particular, the SEQ may result from the orientation of the SEMon the ring to which it is attached, in relation to any other ringand/or moiety attached to the same ring. In one embodiment, the SEM on

is in the ortho position relative to X₁ in Formula I. In anotherspecific embodiment, the SEM is in the meta position relative to X₁.

Thus, in some embodiments, R₂ is alkyl substituted with 1, 2 or 3 halogroups. In some embodiments, R₂ is trifluoromethyl. In still otherembodiments, R₂ is methyl.

In some embodiments, R₃ is absent. For example, in the case of compoundswhere

R₃ would be considered absent, because there no substituents on thering. In other embodiments, R₃ is halogen.

In some embodiments, R₄ is hydrogen. In other embodiments, R₄ is analkyl, e.g., a C₁-C₄ alkyl. For example, in some embodiments, R₄ ismethyl. In some embodiments, R₄ is hydroxymethyl.

In some embodiments, R₅ is hydrogen. In some embodiments, R₆ ishydrogen. In some embodiments, R₅ is an alkyl, e.g., a C₁-C₄ alkyl. Insome embodiments, R₆ is an alkyl, e.g., a C₁-C₄ alkyl.

In some embodiments, R₇ is OH. In other embodiments, R₇ is CO₂H. Instill other embodiments, R₇ is CO₂Me or CO₂Et. In other embodiments, R₇is CO₂-phenyl. In still other embodiments, R₇ is —OP(O)₃H₂. In otherembodiments, R₇ is —CH₂P(O)₃H₂.

In some embodiments,

is phenyl. In other embodiments,

is pyridyl.In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In each of the above structures, R can be hydrogen or alkyl.

In some embodiments,

is pyridyl. In some embodiments,

wherein

indicates the points of attachment of the B ring to the remainder of thecompound.

In some embodiments, compounds of the invention are compounds wherein

R₁ is hydrogen, aryl, cycloalkyl, or heteroaryl.

R₄ is hydrogen, alkyl, alkylene-OH, aryl, -alkylene-O-alkyl,alkylene-CO₂H, or -alkylene-CO₂-alkyl;

R₅ and R₆ are each independently hydrogen or alkyl, or alkylene-OH;

R₇ is selected from the group consisting of OH, alkylene-OH, —CO₂H,alkylene-CO₂H,

-alkylene-CO₂-alkyl, C(O)O-alkyl, —C(O)O-aryl, —CH₂═CHCO₂H,—CH₂═CHC(O)O-alkyl,—CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2), —OPO₃R_(p1)R_(p2),—CH₂PO₃R_(p1)R_(p2), —OPO₂(S)R_(p1)R_(p2), or

—C(Z′)(Z″)PO₃R_(p1)R_(p2).

In some embodiments, compounds of the invention are compounds wherein

R₁ is hydrogen or aryl;

R₄ is hydrogen or alkyl;

R₅ and R₆ are each independently hydrogen or alkyl, or alkylene-OH;

R₇ is selected from the group consisting of —OH, alkylene-OH, —CO₂H,alkylene-CO₂H,

-alkylene-CO₂-ally, C(O)O-alkyl, —C(O)O-aryl, —CH₂═CHCO₂H,—CH₂═CHC(O)O-alkyl,—CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2), —OPO₃R_(p1)R_(p2),—CH₂PO₃R_(p1)R_(p2), —OPO₂(S) R_(p1)R_(p2), and

—C(Z′)(Z″)PO₃R_(p1)R_(p2).

In other embodiments, compounds of the invention are compounds wherein

R₁ is phenyl;

A is (C₁-C₁₀)alkyl;

R′ and R″ are hydrogen;

X₁ is O;

R₄ is hydrogen, alkyl, or alkylene-OH;

R₅ and R₆ are each independently hydrogen, alkyl;

R₇ is selected from the group consisting of —OH, alkylene-OH, —CO₂H,alkylene-CO₂H,

—C(O)O-alkyl, —C(O)O-aryl, —CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl,—CH₂═CHC(O)O-aryl,

—OPO₂R_(p1)R_(p2), —OPO₃R_(p1)R_(p2), —CH₂PO₃R_(p1)R_(p2), —OPO₂(S)R_(p1)R_(p2), and —C(Z′)(Z″)PO₃R_(p1)R_(p2);

In some embodiments, compounds of the invention are compounds of formulaI-1.

Another specific group of compounds of the invention are compounds offormula I-2.

In other aspects, the present invention is directed to a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, or dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, haloalkyl, —CF₃, —CN, —OH, or—O-alkyl;

A is (C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, eachof which may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;

X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl;

R′ and R″ are each independently hydrogen, halogen, alkyl optionallysubstituted on carbon with halogen, alkyl, or taken together with thecarbon to which they are attached form C═O or a 3, 4, 5, or 6-memberedring, optionally containing 1 or 2 heteroatoms selected from ONH,N-alkyl, SO, or SO₂, any of which may be optionally substituted oncarbon with alkyl or halogen

R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino,

—CO-dialkylamino, amino, alkylamino, and dialkylamino, any of which maybe optionally substituted on carbon with 1, 2, or 3 groups selected fromhalo, alkyl, OH, or —O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, alkyl, alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, CO₂-alkyl,alkylene-OC(O)alkyl, cycloalkyl, heterocyclo, —C(O)-alkyl, —C(O)-aryl,C(O)-aralkyl, —C(O)-Oalkyl, —C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino,alkylene-alkylamino, and alkylene-dialkylamino, any of which may beoptionally substituted on carbon with halogen, alkyl, hydroxyl, CO₂H,CO₂alkyl or alkoxy; or

R₅ and R₆, together with the nitrogen to which they are attached, mayform a 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy;

R₇ is selected from the group consisting of —OH, —O-alkyl, -alkylene-OH,—CO₂H, -alkylene-CO₂H, —C(O)O-alkyl, -alkylene-CO₂-alkyl, —C(O)O-aryl,—CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl, —CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2),—OPO₃R_(p1)R_(p2), —CH₂PO₃R_(p1)R_(p2), —OPO₂(S) R_(p1)R_(p2), and—C(Z′)(Z″)PO₃R_(p1)R_(p2), any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein

Z′ is hydroxyl or halogen;

Z″ is H or halogen;

R_(p1) and R_(p2) are each independently hydrogen, C₁-C₆-alkyl, aryl, orone of the following groups:

and

Y is heterocyclo or heteroaryl.

In some embodiments, R₁ is aryl or heteroaryl, optionally substitutedwith 1, 2, or 3 groups selected from halo, alkyl, haloalkyl, -aryl,—CF₃, —CN, —OH, or —O-alkyl. In some embodiments, R₁ is aryl, e.g.,phenyl, optionally substituted with 1 or 2 groups selected from —CF₃,—CN, —OMe, —Cl or —F. In some embodiments, R₁ is heteroaryl, e.g.,thiophene or benzothiophene, optionally substituted with 1 or 2 groupsselected from phenyl, —CF₃, —CN, —OMe, —Cl or —F. In some embodiments,R₁ is hydrogen. In other embodiments, R₁ is phenyl. In some embodiments,R₁ is pyridyl. In other embodiments, R₁ is thiophenyl. In still otherembodiments, R₁ is cyclohexyl. In some embodiments, R₁ is cyclopentyl.

In some embodiments, A is a C₁-C₁₀ alkylene. In some embodiments, A is abranched C₁-C₁₀ alkylene. In other embodiments, A is n-octyl. In otherembodiments, A is n-heptyl. In other embodiments, A is n-hexyl. In someembodiments, A is a C₁-C₅ alkylene. In some embodiments, A is n-pentyl.In other embodiments, A is n-butyl. In still other embodiments, A isn-propyl. In other embodiments, A is ethyl. In still other embodiments,A is methyl.

In some embodiments, X₁ is O. In other embodiments, X₁ is S. In stillother embodiments, X₁ is SO₂. In some embodiments, X₁ is CH₂. In otherembodiments, X₁ is C═O. In still other embodiments, CH₂O, wherein eitherthe oxygen or the carbon may be attached to

In some embodiments, R′ is hydrogen. In other embodiments, R′ is methyl.In some embodiments, R″ is hydrogen. In other embodiments, R″ is methyl.In some embodiments, R′ and R″ taken together with the carbon to whichthey are attached, is C═O, with the provision that only one of X₁ or R′and R″ taken together with the carbon may form C═O.

In some embodiments, R₃ is absent. For example, in the case of compoundswhere

R₃ would be considered absent, because there no substituents on thering. In other embodiments, R₃ is halogen.

In some embodiments, R₄ is hydrogen. In other embodiments, R₄ is analkyl, e.g., a C₁-C₄ alkyl. For example, in some embodiments, R₄ ismethyl. In some embodiments, R₄ is hydroxymethyl.

In some embodiments, R₅ is hydrogen. In some embodiments, R₆ ishydrogen. In some embodiments, R₅ is an alkyl, e.g., a C₁-C₄ alkyl. Insome embodiments, R₆ is an alkyl, e.g., a C₁-C₄ alkyl.

In some embodiments, R₇ is OH. In other embodiments, R₇ is CO₂H. Instill other embodiments, R₇ is CO₂Me or CO₂Et. In other embodiments, R₇is CO₂-phenyl. In still other embodiments, R₇ is —OP(O)₃H₂. In otherembodiments, R₇ is —CH₂P(O)₃H₂.

In some embodiments,

is phenyl. In other embodiments,

is pyridyl.In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In each of the above structures, R can be hydrogen or alkyl.

In some embodiments,

is pyridyl. In some embodiments,

wherein

indicates the points of attachment of the B ring to the remainder of thecompound.

In some embodiments, compounds of formula II are compounds of formulaII-1.

wherein

is a heteroaryl ring containing up to four heteroatoms selected from N,O, or S, optionally substituted on carbon with halogen or alkyl, wherein

Y₁ is CH, N, S, or O;

Y₂ and Y₃ are each independently CH; N, O, or S; provided that when

contains an N—H, that hydrogen may be replaced with alkyl; and

Y₄ is C or N.

In some embodiments, compounds of formula II are compounds of formulaII-2.

In other embodiments, compounds of formula II are compounds of formulaII-3.

In some embodiments, compounds of formula II are compounds of formulaII-4.

In some embodiments, compounds of the present invention includecompounds listed in the following table:

as well as pharmaceutically acceptable salts, phosphate derivatives,phosphate mimics, or phosphate precursor analogs thereof.

In some aspects, the present invention is directed to a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ is hydrogen, halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, —S-alkyl, alkylene-O-alkyl, alkylene-CO₂H,alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl, alkylene-CO-amino,alkylene-CO-alkylamino, alkylene-CO-dialkylamino, alkylene-NH—CO₂H,alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂,—CO-alkylamino, —CO-dialkylamino, amino, alkylamino, or dialkylamino,any of which may be optionally substituted on carbon with 1, 2, or 3groups selected from halo, alkyl, haloalkyl, —CF₃, —CN, —OH, or—O-alkyl;

A is (C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, eachof which may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;

X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl;

R′ and R″ are each independently hydrogen, halogen, alkyl optionallysubstituted on carbon with halogen, alkyl, or taken together with thecarbon to which they are attached form C═O or a 3, 4, 5, or 6-memberedring, optionally containing 1 or 2 heteroatoms selected from ONH,N-alkyl, SO, or SO₂, any of which may be optionally substituted oncarbon with alkyl or halogen

R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted ohcarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, alkyl, alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, CO₂-alkyl,alkylene-OC(O)alkyl, cycloalkyl, heterocyclo, —C(O)-alkyl, —C(O)-aryl,C(O)-aralkyl, —C(O)-Oalkyl, —C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino,alkylene-alkylamino, and alkylene-dialkylamino, any of which may beoptionally substituted on carbon with halogen, alkyl, hydroxyl, CO₂H,CO₂alkyl or alkoxy; or

R₅ and R₆, together with the nitrogen to which they are attached, mayform a 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy;

R₈ is hydrogen, alkyl or aryl; and

n is 0, 1, or 2.

In some embodiments, R₁ is aryl or heteroaryl, optionally substitutedwith 1, 2, or 3 groups selected from halo, alkyl, haloalkyl, -aryl,—CF₃, —CN, —OH, or —O-alkyl. In some embodiments, R₁ is aryl, e.g.,phenyl, optionally substituted with 1 or 2 groups selected from —CF₃,—CN, —OMe, —Cl or —F. In some embodiments, R₁ is heteroaryl, e.g.,thiophene or benzothiophene, optionally substituted with 1 or 2 groupsselected from phenyl, —CF₃, —CN, —OMe, —Cl or —F. In some embodiments,R₁ is hydrogen. In other embodiments, R₁ is phenyl. In some embodiments,R₁ is pyridyl. In other embodiments, R₁ is thiophenyl. In still otherembodiments, R₁ is cyclohexyl. In some embodiments, R₁ is cyclopentyl.

In some embodiments, A is a C₁-C₁₀ alkylene. In some embodiments, A is abranched C₁-C₁₀ alkylene. In other embodiments, A is n-octyl. In otherembodiments, A is n-heptyl. In other embodiments, A is n-hexyl. In someembodiments, A is a C₁-C₅ alkylene. In some embodiments, A is n-pentyl.In other embodiments, A is n-butyl. In still other embodiments, A isn-propyl. In other embodiments, A is ethyl. In still other embodiments,A is methyl.

In some embodiments, X₁ is O. In other embodiments, X₁ is S. In stillother embodiments, X₁ is SO₂. In some embodiments, X₁ is CH₂. In otherembodiments, X₁ is C═O. In still other embodiments, CH₂O, wherein eitherthe oxygen or the carbon may be attached to

In some embodiments, R′ is hydrogen. In other embodiments, R′ is methyl.In some embodiments, R″ is hydrogen. In other embodiments, R″ is methyl.In some embodiments, R′ and R″ taken together with the carbon to whichthey are attached, is C═O, with the provision that only one of X₁ or R′and R″ taken together with the carbon may form C═O.

In some embodiments, R₃ is absent. For example, in the case of compoundswhere

R₃ would be considered absent, because there no substituents on thering. In other embodiments, R₃ is halogen.

In some embodiments, R₄ is hydrogen. In other embodiments, R₄ is analkyl, e.g., a C₁-C₄ alkyl. For example, in some embodiments, R₄ ismethyl. In some embodiments, R₄ is hydroxymethyl.

In some embodiments, R₅ is hydrogen. In some embodiments, R₆ ishydrogen. In some embodiments, R₅ is an alkyl, e.g., a C₁-C₄ alkyl. Insome embodiments, R₆ is an alkyl, e.g., a C₁-C₄ alkyl.

In some embodiments,

is phenyl. In other embodiments,

is pyridyl.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In each of the above structures, R can be hydrogen or alkyl.

In some embodiments,

is pyridyl. In some embodiments,

wherein

indicates the points of attachment of the B ring to the remainder of thecompound.

In some embodiments, compounds of the present invention includecompounds listed in the following table:

wherein n for each compound is 0, 1 or 2, as well as pharmaceuticallyacceptable salts, phosphate derivatives, phosphate mimics, or phosphateprecursor analogs thereof.

Compounds of the present invention include the following compounds:

-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan    1-ol;-   2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propane-1,3-diol;-   (s)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (s)-2-Amino-2-(5-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(decyloxy)-3(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(3-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-(4-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-(3-fluorophenyl)pentyloxy)-34-(trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-((4-phenyl-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(7-phenylheptyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-phenethoxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (s)-2-Amino-2-(5-(4-(3-phenylpropoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzofuran-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzo[b]thiophen-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(benzo[d][1,3]dioxol-5-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(3-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(S-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (2S)-2-Amino-2-(5-(4-(3,7-dimethyloctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-propylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-butylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-ethylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(7,7,8,8,8-pentafluorooctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(2-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(3-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(4-(4-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-(2-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-(3-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-(4-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(5-(3,4-difluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(2,4,5-trifluorophenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(3-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(4-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(octylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(octylsulfonyl)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol;-   (R)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan    1-ol;-   (S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)    thiazol-2-yl)propan-1-ol;    and pharmaceutically acceptable salts, phosphate derivatives,    phosphate mimics, or phosphate precursor analogs thereof.

Compounds of the present invention further include the followingcompounds:

-   (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(octylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(3-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-((4-phenyl-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(5-(3-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(5-(4-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(3-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(4-(4-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(6-(3-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(6-(4-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (s)-2-Amino-2-(5-(4-(5-(3,4-difluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(2,4,5-trifluorophenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl    dihydrogen phosphate;-   (R)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenylisoxazol-5-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl    dihydrogen phosphate;-   (S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyl    dihydrogen phosphate; and-   (S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)    thiazol-2-yl)propyl dihydrogen phosphate.

Biological Activity of Invention Compounds

Lymphopenia Assay

Several of the compounds described herein were evaluated for the abilityto induce lymphopenia in mice. Male C57Bl/6 mice were divided intogroups of three. A control group received the 3% BSA vehicle only. Theother groups received a single dose of either a specified dose of testcompound in vehicle administered orally (PO) and intravenously (IV).After 6 hours, the mice were anesthetized with isoflurane andapproximately 250 μL of blood was removed from the retroorbital sinusand collected in an EDTA microtainer, mixed with an anticoagulant andplaced on a tilt table until complete blood count (CBC) analysis. Oraladministration (10 mg/K) of these compounds induced increasedlymphopenia versus the vehicle.

A 10 mg/Kg oral dose of(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-olproduced a lymphopenia of 75% in this assay.

A 10 mg/Kg oral dose of(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-olproduced a lymphopenia of 77% in this assay.

Binding to S1P-1 or S1P-3 Receptors

In certain embodiments, the compounds of the invention selective for theS1P-1 receptor as compared to one or more of the other S1P receptors.For example, one set of compounds includes compounds which are selectivefor the S1P-1 receptor relative to the S1P-3 receptor. Compoundsselective for the S1P-1 receptor can be agonists of the S1P-1 receptor,significantly weaker agonists of one or more other receptors and/orantagonists of one or more other receptors. A compound is “selective”for the S1P-1 receptor relative to a second receptor, if the EC₅₀ of thecompound for the second receptor is at least two-fold greater than theEC₅₀ for the S1P-1 receptor. The EC₅₀ of a compound is determined usingthe ³⁵S-GTPγS binding assay, as described in WO 03/061567, the entirecontents of which are incorporated herein by reference. Additionally oralternatively, a compound is “selective” for the S1P-1 receptor relativeto a second receptor, if the IC₅₀ of the compound for the secondreceptor is at least two-fold greater than the IC₅₀ for the S1P-1receptor. The IC₅₀ of a compound is determined using the[³³P]sphingosine 1-phosphate binding assay, as described in Davis, M. D.et al., Sphingosine 1-Phosphate Analogs as Receptor Antagonists. J.Biol. Chem. (2005) 280:9833-9841, the entire contents of which areincorporated herein by this reference.

The terms “agonist” or “S1P-1 receptor agonist” as used herein includethe compounds described herein which bind to and/or agonize the S1P-1receptor. In one embodiment, the S1P receptor agonists have an IC₅₀ forthe S1P-1 receptor of about 100 nM-0.25 nM, about 50 nM-0.25 nM, about25 nM-0.5 nM, about 100 nM or less, about 75 nM or less, about 50 nM orless, about 40 nM or less, about 30 nM or less, about 20 nM or less,about 10 nM or less, about 5 nM or less, about 1 nM or less, about 0.5nM or less, or about 0.25 nM or less. The compounds' IC₅₀ for the S1P-1receptor can be measured using the binding assays described in Example13 or those described in WO 03/061567. Compounds of the inventiongenerally had an IC₅₀ in the range of 100 μM (picomolar) to 100 M.

For example,

had an IC₅₀ 3.23 nM

Ranges intermediate to the above recited values are also intended to bepart of this invention. For example, ranges using a combination of anyof the above recited values as upper and/or lower limits are intended tobe included.

In a further embodiment, the S1P receptor agonist has an IC₅₀ value forthe S1P-3 receptor of about 10 nM-10,000 nM, about 100 nM-5000 nM, about100 nM-3000 nM, about 10 nM or greater, about 20 nM or greater, about 40nM or greater, about 50 nM or greater, about 75 nM or greater, or about100 nM or greater. In another embodiment, the S1P compound of theinvention binds the S1P-3 receptor with an IC₅₀ of 1000 nM or greater,2000 nM or greater, 3000 nM or greater, 5000 nM or greater, 10,000 nM orgreater. The IC₅₀ for of S1P-3 receptor can be measured using thebinding assays described herein or those described in WO 03/061567.

In addition, it should be understood that the ranges intermediate to theabove recited values are also intended to be part of this invention. Forexample, ranges using a combination of any of the above recited valuesas upper and/or lower limits are intended to be included.

In yet another embodiment, the S1P receptor agonists described hereinhave an IC₅₀ value for the S1P-1 receptor that is about 5-fold lower,about 10-fold lower, about 20-fold lower, about 50-fold lower, about100-fold lower, about 200-fold lower, about 500-fold lower or about1000-fold lower than their IC₅₀ value for the S1P-3 receptor.

Ranges intermediate to the above recited values are also intended to bepart of this invention. For example, ranges using a combination of anyof the above recited values as upper and/or lower limits are intended tobe included.

The ability of several of the compounds described herein to bind to theS1P-1 or S1P-3 receptor was also tested as follows.

For the membrane preparation, plasmid DNA was transfected into HEK 293 Tcells using the FuGENE 6 transfection protocol (publicly available fromRoche). Briefly, subconfluent monolayers of HEK 293 T cells weretransfected with the DNA mixture containing FuGENE 6 (using a 1:3ratio). The dishes containing the cells were then placed in a tissueculture incubator (5% CO₂, 37° C.). The cells were harvested 48 hoursafter addition of the DNA by scraping in HME buffer (in mM: 20 HEPES, 5MgCl₂, 1 EDTA, pH 7.4, 1 mM PMSF) containing 10% sucrose on ice, anddisrupted using a Dounce homogenizer. After centrifugation at 800×g, thesupernatant was diluted with HME without sucrose and centrifuged at17,000×g for 1 hour. This crude membrane pellet was resuspended in HMEwith sucrose, aliquoted, and snap-frozen by immersion in liquidnitrogen. The membranes were stored at −70° C. Protein concentration wasdetermined spectroscopically by Bradford protein assay.

For the binding assay, [³³P]sphingosine 1-phosphate (obtained fromAmerican Radiolabeled Chemicals, Inc) was added to membranes in 200 μlin 96-well plates with assay concentrations of 2.5 pM [³³P]sphingosine1-phosphate, 4 mg/ml BSA, 50 mM HEPES, pH 7.5, 100 mM NaCl, 5 mM MgCl2,and 5 μg of protein. Binding was performed for 60 minutes at roomtemperature with gentle mixing and terminated by collecting themembranes onto GF/B filter plates. After drying the filter plates for 10minutes, 50 μl of Microscint 40 was added to each well, and filter-boundradionuclide was measured on a Packard Top Count. Nonspecific bindingwas defined as the amount of radioactivity remaining in the presence ofexcess of unlabeled S1P.

GTPgS Assay Protocol

Membrane Preparation

For membrane preparations all steps were performed at 4° C. Rat hepatomacells stably expressing the human S1P1 receptor or Rat BasophilicLeukaemia cells (RBL) stably expressing human S1P3 receptor were grownto 80% confluency before being harvested into 10 ml Phospho-BufferedSaline (PBS) and centrifuged at 1200 rpm for 5 minutes. After removal ofthe supernatant, the pellet was re-suspended and cells were homogenisedwithin a glass Waring blender for 2 bursts of 15 secs in 200 mls ofbuffer (50 mM HEPES, 1 mM leupeptin, 25 ug/ml bacitracin, 1 mM EDTA, 1mM PMSF, 2 uM pepstatin A). The blender was plunged into ice for 5 minsafter the first burst and 10-40 mins after the final burst to allow foamto dissipate. The material was then spun at 500 g for 20 mins and thesupernatant spun for 36 mins at 48,000 g. The pellet was resuspended inthe same buffer as above but without PMSF and pepstatin A. The materialwas then forced through a 0.6 mm needle, made up to the required volume,(usually ×4 the volume of the original cell pellet), aliquoted andstored frozen at −80° C.

GTPgS Assay

Human S1P1 rat hepatoma or S1P3 expressing RBL membranes (1.5 ug/well)were adhered to WGA-coated SPA beads (0.125 mg/well) in assay buffer(HEPES 20 mM, MgCl₂ 3 mM, NaCl 100 mM and pH adjusted to 7.4 using KOH5M, GDP 10 uM FAC and saponin 90 ug/well FAC was also added).

After 30 minutes pre-coupling at 4° C. the bead and membrane suspensionwas dispensed into a white Greiner polypropylene LV384-well plate (5ul/well), containing 0.1 ul of test compound or S1P. 5 ul/well[³⁵S]-GTP□S (0.5 nM final radio-ligand conc) made up in assay buffer wasthen added to the plates. The final assay cocktail (10.1 ul) wascentrifuged at 1000 rpm for 5 minutes then read immediately on aViewlux.

All test compounds were dissolved in DMSO at a concentration of 10 mMand were prepared in 100% DMSO using a 1 in 4 dilution step to provide11 point dose response curves. The dilutions were transferred to theassay plates ensuring that the DMSO concentration was constant acrossthe plate for all assays.

All data was normalized to the mean of 16 high and 16 low control wellson each plate. A four parameter curve fit was then applied.

The trifluoracetic acid salt of(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyldihydrogen phosphate had a pEC50 of 8.5 in the S1P1 assay and pEC50 of6.5 in the S1P3 assay.The trifluoracetic acid salt of(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate had a pEC50 of 9.2 in the S1P1 assay and pEC50 of6.1 in the S1P3 assay.

Methods of Using Invention Compounds

The compounds of the invention have been determined to be useful in thetreatment of sphingosine 1-phosphate associated disorders. Accordingly,in one embodiment, the invention relates to a method for treating asubject suffering from a sphingosine 1-phosphate associated disorder,comprising administering to a subject an effective amount of a compoundof the invention; that is, a compound of formula I or compoundsotherwise described herein, such that the subject is treated for asphingosine 1-phosphate associated disorder.

The term “sphingosine 1-phosphate associated disorder” includesdisorders, diseases or conditions which are associated with or caused bya misregulation in S1P receptor function and/or signaling or S1Preceptor ligand function. The term also includes diseases, disorders orconditions which can be treated by administering to a subject aneffective amount of a sphingosine 1-phosphate receptor agonist. Suchdisorders include disorders that are associated with an inappropriateimmune response and conditions associated with an overactive immuneresponse, e.g., autoimmune diseases. In some embodiments, sphingosine1-phosphate associated disorders include autoimmune diseases. In otherembodiments, sphingosine 1-phosphate associated disorders includeinflammation. In further embodiments, sphingosine 1-phosphate associateddisorders include transplant rejection. In still other embodiments,sphingosine 1-phosphate associated disorders include acute respiratorydistress syndrome (ARDS). In other embodiments, sphingosine 1-phosphateassociated disorders include asthma. In yet other embodiments,sphingosine 1-phosphate associated disorders include any combination ofthe disorders listed herein.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent such as a compound of formula Ito a subject who has a shingosine 1-phosphate associated disorder asdescribed herein, with the purpose to cure, heal, alleviate, delay,relieve, alter, remedy, ameliorate, improve or affect the disease ordisorder, or symptoms of the disease or disorder. The term “treatment”or “treating” is also used herein in the context of administering agentsprophylactically.

In some embodiments, the efficacy of the compounds of the presentinvention can be measured by comparing a value, level, feature,characteristic, property, etc. to a “suitable control”. A “suitablecontrol” is any control or standard familiar to one of ordinary skill inthe art useful for comparison purposes. In one embodiment, a “suitablecontrol” is a value, level, feature, characteristic, property, etc.determined prior to administering a composition of the presentinvention. For example, the immune response, etc. can be determinedprior to introducing a compound of the invention into a cell or subject.In another embodiment, a “suitable control” is a value, level, feature,characteristic, property, etc. determined in a cell or organism, e.g., acontrol or normal cell or organism, exhibiting, for example, normaltraits. In yet another embodiment, a “suitable control” is a predefinedvalue, level, feature, characteristic, property, etc. For example a“suitable control” can be a pre-defined level of binding to a specifiedS1P receptor.

An additional embodiment of the invention pertains to a method fortreating a subject suffering from a sphingosine 1-phosphate associateddisorder, comprising administering to a subject a compound, such thatthe subject is treated for a sphingosine 1-phosphate associated disorderby a compound of the invention; that is, a compound of formulae I orcompounds otherwise described herein.

The present invention is also directed to a method of selectivelytreating a sphingosine 1-phosphate associated disorder, comprisingadministering to a subject an effective amount of a compound of theinvention, e.g., compounds of any of Formulae I-VIII or compoundsotherwise described herein, such that the subject is selectively treatedfor a sphingosine 1-phosphate associated disorder. In certainembodiments, the sphingosine 1-phosphate associated disorder is asphingosine 1-phosphate-(1) associated disorder. In a particularembodiment, the sphingosine 1-phosphate-(1) associated disorder isselectively treated as compared with a sphingosine 1-phosphate-(3)associated disorder.

Another embodiment of the invention is a method of selectively treatinga sphingosine 1-phosphate associated disorder, comprising administeringto a subject a compound, such that the subject is selectively treatedfor a sphingosine 1-phosphate associated disorder by a compound of theinvention, e.g., compounds of any of Formulae I-VIII or compoundsotherwise described herein. In certain embodiments, the sphingosine1-phosphate associated disorder is a sphingosine 1-phosphate-(1)associated disorder. In a particular embodiment, the sphingosine1-phosphate-(1) associated disorder is selectively treated as comparedwith a sphingosine 1-phosphate-(3) associated disorder.

In another embodiment, the present invention provides a method oftreating a condition associated with an activated immune system. Suchdiseases or disorders include multiple sclerosis as well as rejection oftransplanted organs, tissue or cells; graft-versus-host diseases broughtabout by transplantation; autoimmune syndromes including rheumatoidarthritis; systemic lupus erythematosus; antiphospholipid syndrome;Hashimoto's thyroiditis; lymphocytic thyroiditis; myasthenia gravis;type I diabetes; uveitis; episcleritis; scleritis; Kawasaki's disease,uveo-retinitis; posterior uveitis; uveitis associated with Behcet'sdisease; uveomeningitis syndrome; allergic encephalomyelitis; chronicallograft vasculopathy; post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis; inflammatory andhyperproliferative skin diseases; psoriasis; psoriatic arthritis; atopicdermatitis; myopathy; myositis; osteomyelitis; contact dermatitis;eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus;bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema;vasculitis; erythema; cutaneous eosinophilia; acne; scleroderma;alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis;herpetic keratitis; dystrophia epithelialis corneas; corneal leukoma;ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis;Graves' opthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis;pollen allergies; reversible obstructive airway disease; bronchialasthma; allergic asthma; intrinsic asthma; extrinsic asthma; dustasthma; chronic or inveterate asthma; late asthma and airwayhyper-responsiveness; bronchiolitis; bronchitis; endometriosis;orchitis; gastric ulcers; ischemic bowel diseases; inflammatory boweldiseases; necrotizing enterocolitis; intestinal lesions associated withthermal burns; coeliac disease; proctitis; eosinophilic gastroenteritis;mastocytosis; Crohn's disease; ulcerative colitis; vascular damagecaused by ischemic diseases and thrombosis; atherosclerosis; fattyheart; myocarditis; cardiac infarction; aortitis syndrome; cachexia dueto viral disease; vascular thrombosis; migraine; rhinitis; eczema;interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome;hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis;glomerulonephritis; tubulointerstitial nephritis; interstitial cystitis;multiple myositis; Guillain-Barre syndrome; Meniere's disease;polyneuritis; multiple neuritis; myelitis; mononeuritis; radiculopathy;hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cellaplasia; aplastic anemia; hypoplastic anemia; idiopathicthrombocytopenic purpura; autoimmune hemolytic anemia; autoimmunethrombocytopenia; agranulocytosis; pernicious anemia; megaloblasticanemia; anerythroplasia; osteoporosis; fibroid lung; idiopathicinterstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosisvulgaris; photoallergic sensitivity; cutaneous T cell lymphoma;polyarteritis nodosa; Huntington's chorea; Sydenham's chorea;myocardosis; myocarditis; scleroderma; Wegener's granuloma; Sjogren'ssyndrome; adiposis; eosinophilic fascitis; lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis; male patternalopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary'ssyndrome; hypophysitis; chronic adrenal insufficiency; Addison'sdisease; ischemia-reperfusion injury of organs which occurs uponpreservation; endotoxin shock; pseudomembranous colitis; colitis causedby drug or radiation; ischemic acute renal insufficiency; chronic renalinsufficiency; lung solid cancer; malignancy of lymphoid origin; acuteor chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonaryemphysema; cataracts; siderosis; retinitis pigmentosa; senile maculardegeneration; vitreal scarring; corneal alkali burn; dermatitiserythema; ballous dermatitis; cement dermatitis; gingivitis;periodontitis; sepsis; pancreatitis; peripheral artery disease;carcinogenesis; solid cancer tumors; metastasis of carcinoma;hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis;sclerosing cholangitis; partial liver resection; acute liver necrosis;cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepaticfailure; late-onset hepatic failure; “acute-on-chronic” liver failure.

As used herein, the term “subject” includes warm-blooded animals, e.g.,mammals, including humans, cats, dogs, horses, bears, lions, tigers,ferrets, rabbits, mice, cows, sheep, pigs, etc. In a particularembodiment, the subject is a primate. In a specific embodiment, theprimate is a human.

As used herein, the term “administering” to a subject includesdispensing, delivering or applying a compound of the invention in apharmaceutical formulation (as described herein), to a subject by anysuitable route for delivery of the compound to the desired location inthe subject, including delivery by either the parenteral or oral route,intramuscular injection, subcutaneous/intradermal injection, intravenousinjection, buccal administration, topical delivery, transdermal deliveryand administration by the rectal, colonic, vaginal, intranasal orrespiratory tract route.

As used herein, the term “effective amount” includes an amounteffective, at dosages and for periods of time necessary, to achieve thedesired result, e.g., sufficient to treat the condition in a subject. Aneffective amount of a compound of the invention, as defined herein, mayvary according to factors such as the disease state, age, and weight ofthe subject, and the ability of the compound to elicit a desiredresponse in the subject. Dosage regimens may be adjusted to provide theoptimum therapeutic response. An effective amount is also one in whichany toxic or detrimental effects (e.g., side effects) of the compoundare outweighed by the therapeutically beneficial effects.

A therapeutically effective amount of a compound of the invention (i.e.,an effective dosage) may range from about 0.001 to 30 mg/kg body weight,for example, about 0.01 to 25 mg/kg body weight, for example, about 0.1to 20 mg/kg body weight. It is to be understood that all values andranges between those listed are intended to be encompassed by thepresent invention. The skilled artisan will appreciate that certainfactors may influence the dosage required to effectively treat asubject, including but not limited to the severity of the disease ordisorder, previous treatments, the general health and/or age of thesubject, and other diseases present. Moreover, treatment of a subjectwith a therapeutically effective amount of a compound of the inventioncan include a single treatment or, for example, can include a series oftreatments. It will also be appreciated that the effective dosage of thecompound used for treatment may increase or decrease over the course ofa particular treatment.

The methods of the invention further include administering to a subjecta therapeutically effective amount of a compound of the invention incombination with another pharmaceutically active compound known to treatthe disease or condition, e.g., an immunomodulatory agent or ananti-inflammatory agent. Pharmaceutically active compounds that may beused depend upon the condition to be treated, but include as examplescyclosporin, rapamycin, FK506, methotrexate, etanercept, infliximab,adalimumab, non-steroidal anti-inflammatory agents,cyclooxygenase-2-inhibitors, such as celecoxib and rofecoxib, andcorticosteroids. Other suitable compounds can be found in Harrison'sPrinciples of Internal Medicine, Thirteenth Edition, Eds. T. R. Harrisonet al. McGraw-Hill N.Y., N.Y.; and the Physicians Desk Reference 50thEdition 1997, Oradell New Jersey, Medical Economics Co., the completecontents of which are expressly incorporated herein by reference. Thecompound of the invention and the additional pharmaceutically activecompound may be administered to the subject in the same pharmaceuticalcomposition or in different pharmaceutical compositions (at the sametime or at different times).

Pharmaceutical Compositions Comprising Invention Compounds

The present invention also provides pharmaceutically acceptableformulations and compositions comprising one or more compounds of theinvention; that is, compounds of formula I or compounds otherwisedescribed herein. In certain embodiments, the compound of the inventionis present in the formulation in a therapeutically effective amount;that is, an amount effective to treat a sphingosine 1-phosphateassociated disorder.

Accordingly, in one embodiment, the invention pertains to apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention; that is, compounds of formula I orcompounds otherwise described herein, and a pharmaceutically acceptablecarrier.

In another embodiment, the invention is directed to a packagedpharmaceutical composition comprising a container holding atherapeutically effective amount of a compound of the invention; thatis, compounds of formula I or compounds otherwise described herein; andinstructions for using the compound to treat a sphingosine 1-phosphateassociated disorder in a subject.

The term “container” includes any receptacle for holding thepharmaceutical composition. For example, in one embodiment, thecontainer is the packaging that contains the pharmaceutical composition.In other embodiments, the container is not the packaging that containsthe pharmaceutical composition, i.e., the container is a receptacle,such as a box or vial that contains the packaged pharmaceuticalcomposition or unpackaged pharmaceutical composition and theinstructions for use of the pharmaceutical composition. Moreover,packaging techniques are well known in the art. It should be understoodthat the instructions for use of the pharmaceutical composition may becontained on the packaging containing the pharmaceutical composition,and as such the instructions form an increased functional relationshipto the packaged product. However, it should be understood that theinstructions can contain information pertaining to the compound'sability to perform its intended function, e.g., treating, preventing, orreducing a sphingosine 1-phosphate associated disorder in a subject.

Another embodiment of the invention relates to a packaged pharmaceuticalcomposition comprising a container holding a therapeutically effectiveamount of a compound of the invention; that is, a compound of formula Ior compounds otherwise described herein, and instructions for using thecompound to selectively treat a sphingosine 1-phosphate associateddisorder in a subject.

Such pharmaceutically acceptable formulations typically include one ormore compounds of the invention as well as one or more pharmaceuticallyacceptable carriers and/or excipients. As used herein, “pharmaceuticallyacceptable carrier” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like that are physiologically compatible. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. Except insofar as any conventional media or agentis incompatible with the compounds of the invention, use thereof in thepharmaceutical compositions is contemplated.

Supplementary pharmaceutically active compounds known to treattransplant or autoimmune disease, i.e., immunomodulatory agents andanti-inflammatory agents, as described above, can also be incorporatedinto the compositions of the invention. Suitable pharmaceutically activecompounds that may be used can be found in Harrison's Principles ofInternal Medicine.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical),transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injection include sterileaqueous solutions (where water soluble) or dispersions, or sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersions. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEI™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the pharmaceutical composition must be sterile and should befluid to the extent that easy syringability exists. It must also bestable under the conditions of manufacture and storage and must bepreserved against the contaminating action of microorganisms such asbacteria and fingi. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (for example, glycerol,propylene glycol, and liquid polyethylene glycol, and the like), andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms can be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride inthe composition. Prolonged absorption of the injectable compositions canbe brought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating thecompound of the invention in the required amount in an appropriatesolvent with one or a combination of the ingredients enumerated above,as needed, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the compound into a sterile vehicle whichcontains a basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and freeze-drying which yields a powder ofthe compound plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, thecompound of the invention can be incorporated with excipients and usedin the form of tablets, troches, or capsules. Oral compositions can alsoinclude an enteric coating. Oral compositions can also be prepared usinga fluid carrier for use as a mouthwash, wherein the compound in thefluid carrier is applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds of the invention aredelivered in the form of an aerosol spray from a pressured container ordispenser which contains a suitable propellant, e.g., a gas such ascarbon dioxide, or a nebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the compounds of the invention areformulated into ointments, salves, gels, or creams as generally known inthe art.

The present pharmaceutical compositions can also be prepared in the formof suppositories (e.g., with conventional suppository bases such ascocoa butter and other glycerides) or retention enemas for rectaldelivery.

In one embodiment, the compounds are prepared with carriers that willprotect the compound against rapid elimination from the body, such as acontrolled release formulation, including implants and microencapsulateddelivery systems. Biodegradable, biocompatible polymers can be used,such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid,collagen, polyorthoesters, and polylactic acid. Methods for preparationof such formulations will be apparent to those skilled in the art. Thematerials can also be obtained commercially from Alza Corporation andNova Pharmaceuticals, Inc. Liposomal suspensions can also be used aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art, for example, as described inU.S. Pat. No. 4,522,811, U.S. Pat. No. 5,455,044 and U.S. Pat. No.5,576,018, and U.S. Pat. No. 4,883,666, the contents of all of which areincorporated herein by reference.

The compounds of the invention can also be incorporated intopharmaceutical compositions which allow for the sustained delivery ofthe compounds to a subject for a period of at least several weeks to amonth or more. Such formulations are described in published PCTapplication no. WO 02/74247, incorporated herein by reference.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of a compoundof the invention calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the unit dosage forms of the invention are dictated by and directlydependent on the unique characteristics of the compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such compounds for the treatment ofindividuals.

This invention is further illustrated by the following examples, whichshould not be construed as limiting. The contents of all references,patents, patent applications cited throughout this application areincorporated herein by reference. It should be understood that the useof any of the compounds described herein are within the scope of thepresent invention and are intended to be encompassed by the presentinvention and are expressly incorporated herein for all purposes.

EXAMPLES General Approach to the Synthesis of 2,5-DisubstitutedThiazoles

The synthesis of 2,5-substituted thiazoles is described in Scheme 1.Reaction of alcohol R¹—OH wherein R¹ alkyl, aralkyl, heteroaryl,heterocyclo, or cycloalkyl with substituted 4-fluoroacetophenone 1afforded the ether-acetophenone intermediate 2. Ether-acetophenoneintermediate 2 was then converted to the correspondingbromo-acetophenone using Bu₄NBr₃, which, upon reaction with NaN₃,provided the azido-acetophenone intermediate. Hydrogenation of theazido-acetophenone intermediate afforded amine 3, followed by couplingwith orthogonally protected amino acid 4 or amino diol-carboxylic acid 5gave amide 6. As a note, compound 4 was synthesized from(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-2-methylpropanoic acid inthree steps in overall 52-64% yield. A synthesis of(R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acidis described in Clemens, J. J.; Davis, M. D.; Lynch, K. R.; Macdonald,T. L. Bioorg. Med. Chem. Lett. 2005, 15, 3568-3572. Compound 5 wassynthesized from 2-amino-2-(hydroxymethyl)propane-1,3-diol in five stepsin overall 30% yield, also as described in Clemens, J. J.; Davis, M. D.;Lynch, K. R.; Macdonald, T. L. Bioorg. Med. Chem. Lett. 2005, 15,3568-3572. Under conditions using Lawesson's reagent, amide 6 wasconverted to thiazole 7 in good yield. Removal of the protecting groupsafforded the final alcohol 8, which upon reaction with diethylchlorophosphate and subsequent deprotection with TMSBr gave thephosphate 9.

General Protocol for Synthesis of Substituted Acetophenones (WilliamsonEther Synthesis) (2)

To a solution of the desired alcohol (1.0 equivalent) in dry THF undernitrogen atmosphere was added KO^(t)Bu (either 1.0 M solution in THF orsolid, 1.1 equivalent). The reaction mixture was heated at 60-70° C. for10 minutes, then substituted 4-fluoroacetophenone 1 (1.0 equivalent) wasadded. The reaction was then stirred for 1 to 3 hours before cooling toroom temperature (RT). The solvent removed in vacuo. The product waspurified by silica gel column chromatography using the Combi-Flashsystem (Hex:EtOAc).

1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (2)

The product was purified by silica gel column chromatography using theCombi-Flash system (Hex:EtOAc) as white solid in 60% (1.20 g). TLC (1:5EtOAc:Hex), R_(f)=0.4; ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, 1H, J=2.0 Hz),8.10 (dd, 1H, J=8.8 Hz, J=2.3 Hz), 7.02 (d, 1H, J=8.8 Hz), 4.12 (t, 2H,J=6.4 Hz), 2.58 (m, 3H), 1.80-1.89 (m, 2H), 1.42-1.54 (m, 2H), 1.22-1.40(m, 8H), 0.89 (t, 3H, J=6.7 Hz).

2-Amino-1-(4-(octyloxy)-3-(trifluoromethyl)phenyl)ethanone hydrochloride(3)

To a solution of the substituted acetophenone 2 (390 mg, 1.0 equivalent)in dry CH₂Cl₂ (9 mL) under nitrogen atmosphere was added Bu₄NBr₃ (0.60g, 1.0 equiv). To the solution was added anhydrous MeOH (1.0 mL). Thereaction mixture was stirred at room temperature overnight. The solventwas removed in vacuo, and the bromo-acetophenone product was used as isin the next step. TLC (4:1, Hex/EtOAc), R_(f)=0.6.

To the desired bromo-acetophenone (from last step, 1.0 equivalents), inDMF (10 mL) was added NaN₃ (0.24 g, 3.0 equiv). The resulting mixturewas then stirred in DMF for 1 hour. The reaction mixture was dilutedwith EtOAc (50 mL) and washed with H₂O (2×50). The solvent removed invacuo and the product was purified by silica gel column chromatographyusing the Combi-Flash system (Hex:EtOAc) to give the azido-acetophenoneproduct as a white solid in 99% (0.44 g) yield. TLC (4:1, Hex/EtOAc),R_(f)=0.4.

To a solution of the azido-acetophenone (0.44 g, 1.0 equivalent) in MeOH(10 mL) was added concentrated HCl (1.5 mL), and 10% Pd/C (44 mg). Thereaction mixture was stirred under an atmosphere of H₂ (g) for 2 hours.The reaction mixture was then filtered through a thin layer of Celiteand the solvent was removed in vacuo. The amino-acetophenone 3 wasobtained a white solid in quantitative yield (0.46 mg) with 90% purity.TLC (1:5 EtOAc:Hex), R_(f)=0.4; ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, 1H,J=2.0 Hz), 8.10 (dd, 1H, J=8.8 Hz, J=2.3 Hz), 7.02 (d, 1H, J=8.8 Hz),4.52 (s, 2H), 4.12 (t, 2H, J=6.4 Hz), 1.80-1.89 (m, 2H), 1.42-1.54 (m,2H), 1.22-1.40 (m, 8H), 0.89 (t, 3H, J=6.7 Hz).

(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(4)

To a solution of the(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-2-methylpropanoic acid (5.0g, 1.0 equivalent) in CH₂Cl₂/MeOH (4:1, 50 mL) at 0° C. was added asolution of TMS-CHN₂ (2.0 M in diethyl ether or hexanes, 12.5 mL, 1.1equivalents) drop-wise until the colourless solution turned a lightyellow color. The reaction mixture was stirred for 20 minutes then a fewdrops of acetic acid were added to quench the last unreacted TMS-CHN₂(the solution turns colorless from light yellow). The solvent wasremoved in vacuo. TLC (2:1, Hex/EtOAc), R_(f)=0.4.

The residue was dissolved in acetone (30 mL). To the resulting solutionwas then added 2,2-dimethoxypropane (DMP) (15 mL). To the mixture wasadded BF₃.OEt₂ (2 mL) drop-wise and the solution was stirred at RT for4-18 hours. The solvent was removed in vacuo and the product waspurified by silica gel column chromatography using the Combi-Flashsystem (Hex:EtOAc). TLC (3:1, Hex/EtOAc), R_(f)=0.6; ¹H NMR (400 MHz,CDCl₃) δ 4.06-4.12 (m, 1H), 3.73-3.83 (m, 4H), 1.55-1.64 (m, 9H), 1.48(br s, 3H), 1.41 (br s, 6H).

The purified residue was dissolved in THF (40 mL) and to the solutionwas added LiOH (1.15 g, 1.20 equiv) in H₂O (20 mL). The solution washeated at reflux for 6-18 hours, then concentrated in vacuo to removemost of the THF. The solution was diluted with H₂O (150 mL) and washedwith Et₂O (2×150 mL). The aqueous layer was cooled to 0° C. thenacidified to a pH of approximately 3 using concentrated HCl, thenextracted with EtOAc (2×200 mL). The EtOAc layers were combined, dried(MgSO₄), filtered, and the solvent was removed in vacuo to affordcarboxylate 4 as a white solid in 52-64% yield (3.78 g) yield. TLC (1:1EtOAc:Hex), R_(f)=0.2; ¹H NMR (400 MHz, CDCl₃) δ (rotamers) 4.47 (br d,0.5H, J=8.8 Hz), 4.17 (br d, 0.5H, J=8.8 Hz), 3.85 (br d, 0.5H, J=8.8Hz), 3.78 (br d, 0.5H, J=8.8 Hz), 1.38-1.67 (m, 18H).

5-(tert-butoxycarbonylamino)-2,2-dimethyl-1,3-dioxane-5-carboxylic acid(5)

To a solution of the 2-amino-2-(hydroxymethyl)propane-1,3-diol (2.0 g,1.0 equivalent) in DMF (20 mL) at RT was added 1M HCl (16.5 mL, 1.0equiv) in diethyl ether. The resulting mixture was stirred for 20minutes, then para-toluenesulfonic acid (PTSA) (157 mg, 0.05 equivalent)and 2,2-dimethoxypropane or (2.23 mL, 1.1 equivalents) were added. Thereaction mixture was stirred for 24 hours, then Et₃N (3.0 equivalent,6.90 mL) and (Boc)₂O (1.0 equiv, 3.60 g) were added and the mixture wasstirred overnight. The reaction mixture was diluted with EtOAc (50 mL)and washed with H₂O (2×50 mL). The solvent removed in vacuo and theproduct was purified by silica gel column chromatography using theCombi-Flash system (Hex:EtOAc) as a white solid in 58% (2.49 g) yield.TLC (2:1, Hex/EtOAc), R_(f)=0.3; ¹H NMR (400 MHz, CDCl₃) δ 5.33 (br s,1H), 4.27 (br s, 1H), 3.79-3.84 (m, 4H), 3.72 (d, 2H, J=6.4 Hz), 1.46(s, 12H), 1.44 (s, 3H).

To a solution of oxalyl chloride (2.0 M in CH₂Cl₂, 5.74 mL, 3.0equivalents) in dry CH₂Cl₂ (10 mL) at −78° C. was added DMSO (1.36 ml,5.0 equivalents). The resulting mixture was stirred for 15 minutes, thena solution of the desired alcohol (from last step, 1.0 g) in dry CH₂Cl₂(10 mL) was added drop-wise. The mixture was stirred for 2 hours, thenEt₃N (5.33 mL, 10 equivalents) was added. The reaction mixture wasstirred for 10 minutes then the cooling bath was removed and the mixturewas allowed to warm to RT. The reaction mixture was then diluted withEtOAc (50 mL) and washed with 10% NH₄Cl (2×50 mL). The organic layer wasdried over MgSO₄, filtered, and the solvent was removed in vacuo toafford aldehyde intermediate as a white solid in >99% yield (1.00 g).For more detailed Swern oxidatrion conditions see: a) Blaskovich, M. A.;Evindar, G.; Rose, N. G. W.; Wilkinson, S.; Luo, Y.; Lajoie, G. A. J.Org. Chem. 1998, 63, 3631-3646. and b) Rose, N. G. W.; Blaskovich, M.A.; Evindar, G.; Wilkinson, S.; Luo, Y.; Fishlock, D.; Reid, C.; Lajoie,G. A. Organic Syntheses 2002, 79, 216-227. TLC (2:1, Hex/EtOAc),R_(f)=0.7; ¹H NMR (400 MHz, CDCl₃) δ 9.63 (s, 1H), 5.55 (br s, 1H), 4.07(d, 2H, J=12.0 Hz), 3.95 (d, 2H, J=12.0 Hz), 1.47 (s, 18H).

To a solution of the aldehyde (from last step, 1.0 g) in t-BuOH (20 mL)and 2-methyl-2-butene (10 mL) at room temperature was added a solutionof NaH₂PO₄ (1.06 g, 2.0 equivalents), and NaClO₂ (1.40 g, 4.0equivalents) in H₂O (10 mL). The reaction was stirred for 3 hours andthen was diluted with H₂O (10 mL). The mixture was extracted with EtOAc(30 mL). The organic layer was dried over MgSO₄, filtered, and thesolvent was removed in vacuo to afford carboxylate S as a white solid in52% yield (550 mg). For more detailed procedure for oxidation ofaldehyde to carboxylate see: Taylor, R. E.; Galvin, G. M.; Hilfiker, K.A.; Chen, Y. J. Org. Chem. 1998, 63, 9580-9583. TLC (1:1 EtOAc:Hex),R_(f)=0.2; ¹H NMR (400 MHz, CDCl₃) δ 5.50 (br s, 1H), 4.18 (d, 2H,J=11.8 Hz), 4.10 (d, 2H, J=11.8 Hz), 1.47 (br s, 18H).

(R)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)oxazolidine-3-carboxylate(6)

To a solution of protected oxazolidine-4-carboxylic acid 4 (176 mg, 1equivalents), HATU (310 mg, 1.2 equivalents), and DIEA (1.2 mL, 10equivalents) in CH2CL2/DMF (1:1, 10 mL) was added amino-acetophenone 3(250 mg, 1.0 equivalents). The resultant mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with EtOAc (50mL) and washed with 10% NH₄Cl (2×50 mL) and saturated NaCl (1×50 mL).The solvent removed in vacuo and the product was obtained, silica gelcolumn chromatography using the Combi-Flash system (Hex:EtOAc), as awhite solid in 40% yield (185 mg). TLC (1:2 EtOAc:Hex), R_(f)=0.3; MS(ESI, M+Na)=572.99; ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 8.11 (d, 1H,J=8.4 Hz), 7.05 (d, 1H, J=8.4 Hz), 4.62-4.79 (m, 2H), 4.13 (t, 2H, J=6.4Hz), 3.28 (br s, 1H), 1.22-1.90 (m, 30H), 0.89 (t, 3H, J=6.4 Hz).

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(7)

A suspension of protected oxazolidine-amide 6 (180 mg, 1.0 equivalent)and Lawesson's Reagent (390 mg, 3.0 equivalents) in toluene (5 mL) wassealed and heated at 100° C. for 1 hour. After cooling to roomtemperature, the reaction mixture was purified by silica gel columnchromatography using the Combi-Flash system (Hex:EtOAc) as a thickcolourless oil in 67% yield (120 mg). TLC (1:2 EtOAc:Hex), R_(f)=0.8; MS(ESI, M+H⁺)=571.11; ¹H NMR (400 MHz, CDCl₃) δ 7.73 (br s, 1H), 7.70 (s,1H), 7.61 (d, 1H, J=6.8 Hz), 7.01 (d, 1H, J=6.8 Hz), 3.96-4.28 (m, 4H),1.21-1.99 (m, 30H), 0.89 (t, 3H, J=7.6 Hz).

(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol(8a)

A solution of thiazole 7 (120 mg) and para toluenesulfonic acid (PTSA,400 mg, 10 equivalents) in MeOH (6 mL) was refluxed for 6 hours. Thesolvent was removed in vacuo and the product was purified by reversephase preparative HPLC, then lyophilized to dryness to obtain thetrifluoroacetate salt of the product as a white solid in 79% yield (90.5mg). MS (ESI, M+H⁺)=431.01; ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H),7.88 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 7.85 (d, 1H, J=2.4 Hz), 7.34 (d, 1H,J=8.4 Hz), 5.77 (br s, 1H), 4.14 (t, 2H, J=6.4 Hz), 3.76 (dd, 1H,J=11.2, Hz, J=1.2 Hz), 3.66 (dd, 1H, J=11.2 Hz, J=1.2 Hz), 1.73 (q, 2H,J=6.8 Hz), 1.58 (s, 3H), 1.36-1.48 (m, 2H), 1.20-1.36 (m, 8H), 0.85 (t,3H, J=6.4 Hz).

2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propane-1,3-diol(8b)

The diol 8b was prepared from carboxylate S and amino-acetophenone 3analogously to thiazole 8a in 35% yield over three steps. MS (ESI,M+H⁺)=447.01; ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.87 (dd, 1H,J=8.8 Hz, J=2.4 Hz), 7.84 (d, 1H, J=2.4 Hz), 7.32 (d, 1H, J=8.4 Hz),5.71 (br s, 1H), 4.13 (t, 2H, J=6.4 Hz), 3.71-3.85 (m, 4H), 1.72 (q, 2H,J=6.4 Hz), 1.36-1.46 (m, 2H), 1.19-1.35 (m, 8H), 0.84 (t, 3H, J=6.4 Hz).

General Approach to the Synthesis of2,5-Disubstituted-1,3,4-Thiadiazoles

The synthesis of 2,5-substituted thiadiazoles is described in Scheme 2.Reaction of alcohol ROH with substituted 4-fluorobenzoic acid 10afforded ether-benzoate intermediate 11. The ether-benzoate intermediate11 was then coupled with hydrazine to afford benzohydrazide 13. Reactionof benzohydrazide 13 with orthogonally protected amino Note, this phraseused here and elsewhere in the application is new to the acid 4 underusing N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (HATU) followed by cyclization with Lawesson'sreagent provided thiadiazole 14 in good yield. Removal of the protectinggroups afforded final alcohol 15. Alcohol 15 was then converted tocorresponding phosphate as reported in scheme 1.

4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (11a)

To a solution of 1-octanol (315 μL, 2.0 mmol) in anhydrous THF (5 mL)was added potassium t-butoxide (5 mL, 1M solution in THF). The mixturewas heated at 70° C. for 15 min then cooled down to room temperature.4-Fluoro-3-trifluoromethylbenzoid acid (10) (417 mg, 2.0 mmol) in THF (5mL) was added and the resultant was heated at 75° C. overnight. Aftercooling down to room temperature, the reaction mixture was diluted withethyl acetate and washed with water. The water layer was acidified to apH of approximately 3 with HCl (2M) and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated in vacuo to afford the title compound (632 mg, HPLCpurity >95%), which was used for next reaction without furtherpurification. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was3.28 min with gradient 50-98% acetonitrile-H₂O (0.1% trifluoroaceticacid (TFA)) in 3.5 min as mobile phase.

4-(5-Phenylpentyloxy)-3-(trifluoromethyl)benzoic acid (11b)

The title compound was prepared analogously to4-(octyloxy)-3-(trifluoromethyl)benzoic acid (11a) in >95% yield. HPLCretention time on a C8(2) column (30×3.00 mm, 3μ) is 3.31 min withgradient 20-98% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.

4-(4-Phenylbutoxy)-3-(trifluoromethyl)benzoic acid (11c)

The title compound was prepared analogously to4-(octyloxy)-3-(trifluoromethyl)benzoic acid (11a) in >95% yield. HPLCretention time on a C8(2) column (30×3.00 mm, 3μ) is 3.14 min withgradient 20-98% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.

4-(Octyloxy)-3-(trifluoromethyl)benzohydrazide (12a)

4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (11a) (632 mg, crude,approximately 1.89 mmol) was stirred with HATU (905 mg) and DIEA (1.7mL) in CH₂Cl₂-DMF (10 mL, 4:1) for 10 min followed by addition ofhydrazine (297 μL) dropwise. The reaction mixture was continuouslystirred for another hour, then was diluted with ethyl acetate (30 mL)and washed with water (10 mL) and brine (3×15 mL). The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to afford the title compound(661 mg, HPLC purity >90%), which was used for next reaction withoutfurther purification. MS (ESI): 333.08 (MH⁺); HPLC retention time on aC8(2) column (30×3.00 mm, 3μ) is 1.61 min with gradient 50-98%acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.

4-(5-Phenylpentyloxy)-3-(trifluoromethyl)benzohydrazide (12b)

The title compound was prepared analogously to4-(octyloxy)-3-(trifluoromethyl)-benzo-hydrazide (12a) in >95% yield. MS(ESI): 367.14 (MH⁺); HPLC retention time on a C8(2) column (30×3.00 mm,3μ) is 2.44 min with gradient 20-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase.

4-(4-Phenylbutoxy)-3-(trifluoromethyl)benzohydrazide (12c)

The title compound was prepared analogously to4-(octyloxy)-3-(trifluoromethyl)-benzo-hydrazide (12a) in >95% yield. MS(ESI): 353.11 (MH⁺); HPLC retention time on a C8(2) column (30×3.00 mm,3μ) is 2.30 min with gradient 20-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase.

(S)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(13a)

(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(4) (210 mg, 0.81 mmol) was stirred with HATU (372 mg, 0.98 mmol) anddiisopropylethyl amine (DIEA) (0.705 mL, 4.1 mmol) in CH₂Cl₂-DMF (2:1, 6mL) for 10 min followed by addition of4-(octyloxy)-3-(trifluoromethyl)benzohydrazide (12a) (270 mg, 0.81 mmol)in CH₂Cl₂ (2 mL). The reaction was stirred at room temperature for 1hour and then was concentrated under vacuum. The residue was dilutedwith ethyl acetate (20 mL) and washed with water (5 mL), brine (2×10 mL)and dried over Na₂SO₄. The organic layer was concentrated in vacuo andchromatographed on a silica gel column (ethyl acetate-hexane, 0-33%, aseluent) to afford the title compound (428 mg, 82% yield). MS (EST):573.84 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ 9.43 (br, 2H), 8.06 (d, 1H,J=2.0 Hz), 7.94 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 6.96 (d, 1H, J=8.8 Hz),4.52 (br, 1H), 4.07 (t, 2H, J=6.4 Hz), 3.76 (br, 1H), 1.82 (m, 2H), 1.67(s, 6H), 1.57 (s, 3H), 1.51 (s, 9H), 1.51-1.43 (m, 4H), 1.38-1.24 (m,6H), 0.88 (t, 3H, J=7.2 Hz).

(S)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate(13b)

The title compound was prepared analogously to (s)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(13a) in 95% yield. MS (ESI): 607.81 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ9.94 (br, 1H), 9.04 (br, 1H), 8.05 (d, 1H, J=2.4 Hz), 7.93 (dd, 1H,J=8.8 Hz, J=2.4 Hz), 7.29-7.25 (m, 2H), 7.18-7.15 (m, 3H), 6.97 (d, 1H,J=8.8 Hz), 4.55 (br, 1H), 4.07 (t, 2H, J=6.4 Hz), 3.77 (br, 1H), 2.64(d, 2H, J=7.6 Hz), 1.86 (m, 2H), 1.73-1.65 (m, 9H), 1.58-1.52 (m, 13H).

(S)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(4-phenylbutoxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(13c)

The title compound was prepared analogously to (S)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(13a) in 97% yield. MS (ESI): 593.87 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ9.94 (br, 1H), 8.79 (br s, 1H), 8.05 (d, 1H, J=2.4 Hz), 7.93 (dd, 1H,J=8.8 Hz, J=2.4 Hz), 7.30-7.25 (m, 2H), 7.20-7.16 (m, 3H), 6.98 (d, 1H,J=8.8 Hz), 4.55 (br, 1H), 4.10 (t, 2H, J=6.4 Hz), 3.78 (br s, 1H), 2.69(d, 2H, J=7.6 Hz), 1.86 (m, 4H), 1.68 (s, 6H), 1.58 (s, 3H), 1.52 (s,9H).

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(14a)

A solution of (S)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate(13a) (228 mg, 0.39 mmol) in toluene (5 mL) was treated with Lawesson'sreagent (473 mg, 1.17 mmol) at 85° C. for 2 hours. The reaction wascooled down to room temperature and the supernatant was chromatographedon a silica gel column eluted with ethyl acetate-hexane (0-30%, v/v) toafford the title compound (156 mg, 70% yield). MS (ESI): 572.17 (MH⁺),¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, 1H, J=8.8 Hz), 8.08 (d, 1H, J=6.8Hz), 7.06 (d, 1H, J=8.0 Hz), 4.41 (d, 1H, J=8.0 Hz), 4.18 (d, 1H, J=9.6Hz), 4.13-4.07 (m, 3H), 2.00 (s, 3H), 1.85 (m, 2H), 1.78 (s, 3H), 1.68(m, 4H), 1.51 (s, 3H), 1.47 (m, 2H), 1.39-1.28 (m, 13H), 0.89 (t, 3H,J=7.2 Hz).

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)-phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(14b)

The title compound was prepared analogously to (R)-tert-butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(14a) in 80% yield. MS (ESI): 606.19 (MH⁺), HPLC retention time on aC8(2) column (30×3.00 mm, 3μ) is 3.78 min with gradient 50-98%acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(14c)

The title compound was prepared analogously to (R)-tert-butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(14a) in 75% yield. MS (ESI): 592.14 (MH⁺), HPLC retention time on aC8(2) column (30×3.00 mm, 3μ) is 3.55 min with gradient 50-98%acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase

(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(15a)

A solution of (S)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate(14a) (156 mg, 0.27 mmol) in methanol (5 mL) was treated withp-toluenesulfonic acid monohydrate (259 mg, 1.36 mmol) at 70° C. for 2hours. The reaction mixture was then cooled to room temperature andpurified by prep HPLC on a C8(2) column ((Luna, 5μ, 100×21.10 mm) withacetonitrile-H₂O (0.1% TFA) as mobile phase and gradient 30-98% in 20min. The title compound was obtained as the bis-TFA salt (36 mg, 20%).MS (ESI). 432.00 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 8.21 (dd, 1H, J=2.0Hz, J=8.8 Hz), 8.15 (d, 1H, J=2.0 Hz), 8.09 (br s, 2H), 7.45 (d, 1H,J=8.8 Hz), 5.96 (t, 1H, J=4.8 Hz), 4.21 (t, 2H, J=6.4 Hz), 3.81 (dd, 1H,J=11.2 Hz, J=5.2 Hz), 3.73 (dd, 1H, J=11.2 Hz, J=5.2 Hz), 1.76 (m, 2H),1.66 (s, 3H), 1.44 (m, 2H), 1.28 (m, 8H), 0.86 (t, 3H, J=6.8 Hz).

(S)-2-Amino-2-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(15b)

The title compound was prepared analogously to(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(15a) in 67% yield. MS (ESI): 466.05 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (br s, 2H), 8.22 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 8.16 (d, 1H, J=2.0Hz), 7.45 (d, 1H, J=8.8 Hz), 7.26 (t, 2H, J=7.6 Hz), 7.20-7.14 (m, 3H),6.10 (br, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.83 (d, 1H, J=11.2 Hz), 3.77 (d,1H, J=11.2 Hz), 2.59 (t, 2H, J=7.2 Hz), 1.80 (m, 2H), 1.70 (s, 3H), 1.46(m, 2H), 1.46 (m, 2H).

(S)-2-Amino-2-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(15c)

The title compound was prepared analogously to(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(15a) in 70% yield. MS (ESI): 452.06 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ8.60 (br s, 2H), 8.23 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 8.16 (d, 1H, J=2.4Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (t, 2H, J=7.2 Hz), 7.21-7.15 (m, 3H),4.25, 4.22 (t, 2H, J=5.6 Hz), 3.82 (d, 1H, J=9.6 Hz), 3.75 (d, 1H, J=9.6Hz), 2.65 (t, 2H, J=7.2 Hz), 1.80-172 (m, 4H), 1.68 (s, 3H).

General Method for Phosphate Synthesis

Synthetic strategy for synthesis of desired phosphates is illustrated inScheme 1 above. To a solution of unprotected amino alcohol (1.0 equiv)in dry CH₂Cl₂ at room temperature was added excess diethylchlorophosphate (10.0 equiv) and triethylamine (20.0 equivalents) andthe reaction stirred for 12-18 hours. The reaction was monitored byLC-MS. The crude reaction mixture was then evaporated to dryness invacuo. The obtained phospho-diester intermediate was reacted with excessbromotrimethylsilane (10.0-20.0 equiv) in dry CH₂Cl₂ at room temperatureover a period of 6-10 hours to afford the final phosphate which waspurified by reverse-phase preparative HPLC after evaporation of thesolvent and excess reagent.

(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyldihydrogen phosphate (9a)

The product was obtained as a white solid in 28% (10 mg) yield from thealcohol precursor. MS (ESI, M+H⁺)=511.1.

(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (16a)

MS (ESI): 511.98 (MH⁺), HPLC retention time on a C8(2) column (30×3.00mm, 3μ) is 1.88 min with gradient 40-98% acetonitrile-H₂O (0.1% TFA) in3.5 min as mobile phase.

(S)-2-Amino-2-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (16b)

MS (ESI): 546.01 (MH⁺), HPLC retention time on a C8(2) column (30×3.00mm, 3μ) is 2.06 min with gradient 30-98% acetonitrile-H₂O (0.1% TFA) in3.5 min as mobile phase.

(S)-2-Amino-2-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (16c)

MS (ESI): 532.01 (MH⁺), HPLC retention time on a C8(2) column (30×3.00mm, 3μ) is 1.96 min with gradient 30-98% acetonitrile-H₂O (0.1% TFA) in3.5 min as mobile phase.

General Approach to Synthesis of Compounds of Formula III

The synthesis of compounds of formula III is described in Scheme 3.Synthesis of compounds 1a and 1b in strategy A and compound 3 instrategy B were described in schemes 1 and 2. Oxidation of the compounds1a and 1b in strategy A followed by deprotection afforded compounds 2aand 2b. In strategy B, coupling of the free amine in compound 3 with thedesired protected-amino acid gave compound 4 which upon cyclizationunder Lawesson's reagent conditions provided the desired azole 5.Removal of the protecting groups afforded the final carboxylate 6.

General Approach to Synthesis of Ether-Phenyl-Thiadiazoles

Synthesis of phenyl-thiazoles is described in Scheme 4. Reaction ofbenzyl or allyl alcohol with substituted 4-fluorobenzoic acid 1 affordedthe substituted ether-benzoate 2. The substituted ether-benzoate 2 wasthen coupled with hydrazine to afford benzohydrazide 3. Reaction ofbenzohydrazide 3 with orthogonally protected amino acid 4 under HATUconditions followed by cyclization and deprotection (or vis versa)provided phenol 6 in good yield. Mitsunobu reaction of phenol 6 withdesired alcohol followed by deprotection afforded the desired finalcompound 8. Reaction of the alcohol 8 with diethyl chlorophosphatefollowed by deprotection with TMSBr gave the corresponding phosphate.

General Procedure for Preparation of Substituted Phenyl Alcohols

Various starting material alcohols for Mitsunobu reaction were preparedas described below.

General Procedure for Sonogashira Cross-Coupling

To a mixture of a substituted 4-iodobenzene (1.0 equiv), Pd(PPh₃)₄ (0.02equiv) and CuI (0.04 equiv) in MeCN was added the alkynol (1.5 equiv)and Et₃N (1.5 equiv). The reaction mixture was stirred for 2-16 hours atreflux, then the solvent removed in vacuo. The crude product waspurified by silica gel column chromatography using the Combi-Flashsystem (Hex:EtOAc) as needed.

General Method for Hydrogenation of Alkyne

The desired alkyne is dissolved in ethanol and a heterogeneous mixtureof palladium on carbon is added. The reaction is shaken for 2 hoursunder 40 psi of H₂. Filtration through celite and removal of the solventin vacuo gives the desired product.

6-Phenylhexan-1-ol

The title compound was prepared from 6-phenylhex-S-yn-1-ol in 70% (241mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.18-7.27 (m, 2H), 7.16-7.18 (m,3H) 3.63 (t, 2H, J=6.4 Hz), 2.61 (t, 2H, J=8.0 Hz), 1.56-1.69 (m, 4H),1.37-1.40 (m, 5H).

5-(3-(Trifluoromethyl)phenyl)pentan-1-ol

The title compound was prepared from5-(3-(trifluoromethyl)phenyl)pent-4-yn-1-ol in 85% (241 mg) yield. ¹HNMR (400 MHz, CDCl₃) δ 7.36-7.42 (m, 4H), 3.65 (t, 2H, J=6.8 Hz), 2.68(t, 2H, J=6.0 Hz), 1.59-1.68 (m, 4H), 1.37-1.44 (m, 3H).

5-(4-(Trifluoromethyl)phenyl)pentan-1-ol

The title compound was prepared from5-(4-(trifluoromethyl)phenyl)pent-4-yn-1-ol in 60% (140 mg) yield. ¹HNMR (400 MHz, CDCl₃) δ 7.52 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=7.3 Hz),3.64 (t, 2H, J=6.8 Hz), 2.68 (t, 2H, J=8.0 Hz), 1.57-1.70 (m, 4H),1.39-1.45 (m, 3H).

4-(4-(Trifluoromethyl)phenyl)butan-1-ol

The title compound was prepared from4-(4-(trifluoromethyl)phenyl)but-3-yn-1-ol in 28% (183 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 7.53 (d, 2H, J=8.0 Hz), 7.29 (d, 2H, J=7.6 Hz), 3.67(t, 2H, J=6.4 Hz), 2.71 (t, 2H, J=7.6 Hz), 1.69-1.76 (m, 2H), 1.59-1.64(m, 3H).

4-(3-(Trifluoromethyl)phenyl)butan-1-ol

The title compound was prepared from4-(3-(trifluoromethyl)phenyl)but-3-yn-1-ol in 70% (453 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 7.26-7.67 (m, 4H), 3.67 (t, 2H, J=6.4 Hz), 2.70 (t,2H, J=6.4 Hz), 1.71-1.92 (m, 2H), 1.57-1.70 (m, 3H).

5-(3-Fluorophenyl)pentan-1-ol

The title compound was prepared from 5-(3-fluorophenyl)pent-4-yn-1-ol in73% (405 mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.26 (m, 1H), 6.94(d, 1H, J=7.6 Hz), 6.84-6.88 (m, 2H), 3.64 (t, 2H, J=6.8 Hz), 2.62 (t,2H, J=7.6 Hz), 1.56-1.69 (m, 4H), 1.36-1.46 (m, 5H).

5-(4-Fluorophenyl)pentan-1-ol

The title compound was prepared from 5-(4-fluorophenyl)pent-4-yn-1-ol in60% (325 mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.13 (m, 2H),6.93-6.97 (m, 2H), 3.64 (t, 2H, J=6.8 Hz), 2.59 (t, 2H, J=7.2 Hz),1.56-1.66 (m, 5H), 1.37-1.43 (m, 4H).

4-(2-Fluorophenyl)butan-1-ol

The title compound was prepared from 4-(2-fluorophenyl)but-3-yn-1-ol in50% (246 mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.25 (m, 2H),6.97-7.03 (m, 2H), 3.66 (t, 2H, J=6.0 Hz), 2.68 (t, 2H, J=6.8 Hz),1.59-1.73 (m, 4H), 1.37 (br s, 1H).

4-(3-Fluorophenyl)butan-1-ol

The title compound was prepared from 4-(3-fluorophenyl)but-3-yn-1-ol in60% (295 mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.19-7.29 (m, 1H), 6.95(d, 1H, J=7.2 Hz), 6.83-6.89 (m, 2H), 3.66 (t, 2H, J=6.4 Hz), 2.64 (t,2H, J=7.6 Hz), 1.56-1.74 (m, 4H), 1.39 (br s, 1H).

4-(4-Fluorophenyl)butan-1-ol

The title compound was prepared from 4-(4-fluorophenyl)but-3-yn-1-ol in47% (233 mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.10-7.15 (m, 2H),6.93-6.98 (m, 2H), 3.66 (t, 2H, J=6.4 Hz), 2.61 (t, 2H, J=7.6 Hz),1.56-1.72 (m, 4H), 1.35 (s, 1H).

6-(4-Fluorophenyl)hexan-1-ol

The title compound was prepared from 6-(4-fluorophenyl)hex-5-yn-1-ol in17% (95 mg) yield. ¹H NMR (400 MHz, CDCl₃) δ 7.15-7.18 (m, 2H),6.98-7.07 (m, 2H), 3.65 (t, 2H, 6.8 Hz), 2.65 (t, 2H, J=7.6 Hz),1.57-1.65 (m, 4H), 1.38-1.42 (m, 4H), 1.31 (s, 1H).

6-(3-fluorophenyl)hexan-1-ol

The title compound was prepared from6-(3-(trifluoromethyl)phenyl)hex-5-yn-1-ol in 17% (100 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 7.19-7.25 (m, 1H), 6.93 (d, 1H, J=8.0 Hz), 6.83-6.88(m, 2H), 3.63 (t, 2H, J=6.4 Hz), 2.60 (t, 2H, J=7.6 Hz), 1.53-1.66 (m,4H), 1.31-1.43 (m, 5H)

6-(4-fluorophenyl)hexan-1-ol

The title compound was prepared from6-(3-(trifluoromethyl)phenyl)hex-5-yn-1-ol in 27% (162 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 7.19-7.27 (m, 1H), 7.09-7.13 (m, 1H), 6.92-7.04 (m,2H), 3.63 (t, 2H, J=6.4 Hz), 2.57 (t, 2H, J=7.6 Hz), 1.49-1.66 (m, 5H),1.34-1.42 (m, 4H).

5-(3,4-difluorophenyl)pentan-1-ol

The title compound was prepared from6-(3-(trifluoromethyl)phenyl)hex-5-yn-1-ol in 67% (404 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 6.93-7.05 (m, 2H), 6.84-6.87 (m, 1H), 3.64 (t, 2H,J=6.8 Hz), 2.58 (t, 2H, J=7.6 Hz), 1.56-1.66 (m, 4H), 1.35-1.43 (m, 3H)

5-(2,4,5-trifluorophenyl)pentan-1-ol

The title compound was prepared from6-(3-(trifluoromethyl)phenyl)hex-5-yn-1-ol in 57% (0.376 g) yield. ¹HNMR (400 MHz, CDCl₃) δ 6.96-7.01 (m, 1H), 6.83-6.89 (m, 1H), 3.64 (t,2H, J=6.8 Hz), 2.59 (t, 2H, J-7.2 Hz), 1.56-1.65 (m, 4H), 1.34-1.44 (m,3H)

6-(3-(trifluoromethyl)phenyl)hexan-1-ol

The title compound was prepared from6-(3-(trifluoromethyl)phenyl)hex-5-yn-1-ol in 50% (362 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 7.33-7.44 (m, 4H), 3.64 (t, 2H, J=6.8 Hz), 2.67 (t,2H, J=7.2 Hz), 1.54-1.69 (m, 4H), 1.24-1.44 (m, 5H).

6-(4-(trifluoromethyl)phenyl)hexan-1-ol

The title compound was prepared from6-(4-(trifluoromethyl)phenyl)hex-5-yn-1-ol in 72% (534 mg) yield. ¹H NMR(400 MHz, CDCl₃) δ 7.52 (d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 3.64(t, 2H, J=6.4 Hz), 2.66 (t, 2H, J=7.2 Hz), 1.53-1.68 (m, 4H), 1.35-1.42(m, 5H).

General Protocol for Synthesis of Substituted 4-(Allyloxy)Benzoic Acid(2)

To a solution of the desired alcohol (1.05 equiv) in anhydrous THF wasadded potassium t-butyloxide (2.05 equiv). The mixture was heated at 65°C. for 10 minutes then added substituted 4-fluorobenzoic acid (1) (1.00equiv) in THF. The resultant solution was heated at 65° C. 1 to 3 hours.After cooling down to room temperature, the reaction was diluted withethyl acetate and washed with 10% KHSO₄ or 1N HCl (1×), and saturatedNaCl (1×). The organic layer was dried over MgSO₄, filtered, and thesolvent was removed in vacuo to afford intermediate 2.

4-(Allyloxy)-3-(trifluoromethyl)benzoic acid (2a)

The title compound was prepared from 4-fluoro-3-(trifluoromethyl)benzoicacid (1a) in >99% (5.65 g) yield. HPLC retention time on a C8(2) column(30×3.00 mm, 3μ) was 2.53 min with gradient 20-98% acetonitrile-H₂O(0.1% TFA) in 4.0 min as mobile phase. ¹H NMR (400 MHz, DMSO-d₆) δ 13.10(br s, 1H), 8.15 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 8.08 (d, 1H, J=2.4 Hz),7.35 (d, 1H, J=8.8 Hz), 5.95-6.80 (m, 1H), 5.38-5.45 (m, 1H), 5.26-5.32(m, 1H), 4.77-4.82 (m, 2H).

4-(Benzyloxy)-3-(trifluoromethyl)benzoic acid (2b)

The title compound was prepared from 4-fluoro-3-(trifluoromethyl)benzoicacid (1a) in >99% (7.22 g) yield.

General Protocol for Synthesis of Substituted Benzohydrazide (3)

Benzoic acid 2 (1.0 equiv) was stirred with HATU (1.1 equiv) and DIEA(3.0 equiv) in DCM-DMF (2:1) for 20 minutes. The solution was then addedto a solution of hydrazine mono-hydrate (3.0-5.0) in DCM-DMF (2:1). Thereaction mixture was stirred at rt for 1 hour, then diluted with ethylacetate and washed with 10% NH₄Cl (2×) and saturated NaCl (1×). Theorganic layer was dried over MgSO₄, filtered, and the solvent wasremoved in vacuo to afford benzohydrazide 3.

4-(Allyloxy)-3-(trifluoromethyl)benzohydrazide (3a)

The title compound was prepared from4-(allyloxy)-3-(trifluoromethyl)benzoic acid (1a) in >99% (6.00 g)yield. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was 1.79min with gradient 20-98% acetonitrile-H₂O (0.1% TFA) in 4.0 min asmobile phase. MS (ESI, M+H⁴)=261.09

4-(Benzyloxy)-3-(trifluoromethyl)benzohydrazide (3b)

The title compound was prepared from4-(Benzyloxy)-3-(trifluoromethyl)benzoic acid 2b in >99% (14.7 g) yield.MS (ESI, M+H⁺)=311.1.

General Protocol for Synthesis of Acyl-Benzohydrazide (5)

(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid4 (1.0 equiv) was stirred with HATU (1.1 equiv) and DIEA (3.0 equiv) inDCM-DMF (2:1) for 10 min followed by addition of substitutedbenzohydrazide 3 (1.0 equiv). The reaction mixture was stirred at rt for1 hour, then diluted with ethyl acetate and washed with 10% NH₄Cl (2×)and saturated NaCl (1×). The organic layer was dried over MgSO₄,filtered, and the solvent was removed in vacuo to affordacyl-benzohydrazide 5.

(R)-tert-Butyl4-(2-(4-(allyloxy)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)-2,2,4-trimethyloxazolidine-3-carboxylate(5a)

The title compound was prepared from4-(allyloxy)-3-(trifluoromethyl)benzohydrazide 3a in >99% (11.51 g)yield. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was 2.92min with gradient 20-98% acetonitrile-H₂O (0.1% TFA) in 4.0 min asmobile phase. MS (ESI, M+Na⁺)=524.1

(R)-tert-Butyl4-(2-(4-(benzyloxy)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)-2,2,4-trimethyloxazolidine-3-carboxylate(5b)

The title compound was prepared from4-(benzyloxy)-3-(trifluoromethyl)benzohydrazide 3b in 83% (13.1 g)yield. MS (ESI, M+Na⁺)=574.1; TLC (2:1, Hex/EtOAc), R_(f)=0.34.

General Protocol for Synthesis of Phenyl-Thiadiazole from AllylProtected Precursor (6)

A solution of allyl protected acyl-benzohydrazide 5a (1.0 equiv) in DCMwas treated with Lawesson's reagent (1.0 equiv) at 50° C. overnight. Thereaction was cooled down to room temperature and the supernatant waschromatographed on a silica gel column eluted with ethyl acetate inhexanes (0-40%, v/v) to afford phenyl-thiadiazole.

A solution of phenyl-thiadiazole (1.0 equiv) and Et₂NH (1.5 equiv) inTHF was treated with Pd(PPh₃)₄ (0.02 to 0.05 equiv) at rt for 1-3 hours.The solvent removed in vacuo and the product was purified by silica gelcolumn chromatography using the Combi-Flash system (Hex:EtOAc).

(R)-tert-Butyl4-(5-(4-(allyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate

The title compound was prepared from acyl-benzohydrazide 5a in 88% (8.35g) yield. HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) was2.84 min with gradient 50-98% acetonitrile-H₂O (0.1% TFA) in 4.0 min asmobile phase. MS (ESI, M+H⁺)=500.0; ¹H NMR (400 MHz, DMSO-d₆) δ8.13-8.24 (m, 2H), 7.42 (d, 1H, J=8.4 Hz), 5.98-6.10 (m, 1H), 5.40-5.50(m, 1H), 5.25-5.34 (m, 1H), 4.80-4.84 (m, 2H), 4.10-4.40 (m, 2H), 1.88(s, 3H), 1.66 (s, 3H), 1.56 (s, 3H), 1.41 (s, 3H), 1.18 (s, 6H).

(R)-tert-Butyl4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate(6a)

The title compound was prepared from allyl protected phenyl-thiadiazole6a in 64% (4.86 g) yield. HPLC retention time on a C8(2) column (30×3.00mm, 3μ) was 2.06 min with gradient 50-98% acetonitrile-H₂O (0.1% TFA) in4.0 min as mobile phase. MS (ESI, M+H⁺)=460.0; ¹H NMR (400 MHz, DMSO-d₆)δ 11.40 (s, 1H), 8.00-8.10 (m, 21H), 7.18 (d, 1H, J=8.8 Hz), 4.07-4.21(m, 2H), 1.88 (s, 3H), 1.67 (s, 3H), 1.57 (s, 3H), 1.42 (s, 3H), 1.19(s, 6H).

(R)-tert-Butyl4-(2-(4-hydroxy-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)-2,2,4-trimethyloxazolidine-3-carboxylate(5c)

A solution of benzyl protected acyl-benzohydrazide 5b (1.0 equiv) inMeOH was subjected to hydrogenation in the presence of Pd/C (10% w) for1 h. The reaction mixture was filtered through celite and concentratedto give compound 5c (6.86 g, 99% yield). MS (ESI, M+Na⁺): 484.0; TLC(2:1, Hex/EtOAc), R_(f)=0.20; ¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 1H,),7.95 (d, 1H, J=8.8 Hz), 7.01 (d, 1H, J=8.8 Hz), 4.28 (br s, 1H), 3.91(br s, 1H), 1.69 (s, 3H,), 1.64 (s, 3H), 1.58 (s, 3H), 1.49 (s, 9H).

(R)-tert-Butyl4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyloxazolidine-3-carboxylate(6a)

The phenyl-thiazole 6a was prepared through two different protocols (Aand B) from 5c:

Protocol A:

A solution of acyl-benzohydrazide 5c (1 equiv) in DCM was treated withLawesson's reagent (3.0 equiv) at 50° C. overnight. The reaction wascooled down to room temperature and the supernatant was chromatographedon a silica gel column eluted with ethyl acetate in hexanes (0-40%, v/v)to afford phenyl-thiadiazole 6 in 37% (670 mg) yield.

Protocol B:

A solution of acyl-benzohydrazide 5c (1 equiv) in DCM was added acetylanhydride (1.1 equiv) and pyridine (1.1 equiv). The mixture was stirredat rt for 4 h. The solvent was removed under vacuum and the residue wasdissolved in ethyl acetate, washed with brine (3×), dried over MgSO₄ andconcentrated to afford crude acylated 5c in quantitative (5.46 g) yield.TLC (4:1, Hex/EtOAc), R_(f)=0.40; MS (ESI, M+H⁺)=504.1.

To a solution of acylated intermediate 5c (1.0 equiv) in toluene wasadded Lawesson's reagent (1.1 equiv). The mixture was heated at 85° C.for 3 h. The reaction was cooled down to room temperature and thesupernatant was chromatographed on a silica gel column eluted with ethylacetate in hexanes (15%-30%, v/v) to afford acylated 6a in 82% (5.1 g)yield. MS (ESI, M+H⁺)=502.0.

Acylated 6a was dissolved in a mixture of methanol and saturated NaHCO₃(2:1, v/v) and stirred at rt overnight. The methanol was removed and theaqueous phase was extracted with ethyl acetate (3×). The combinedorganic phase was washed with brine, dried over MgSO₄ and concentratedto afford 6a in 76% (3.1 g) yield.

General Protocol for Mitsunobu Reaction (7)

To a suspension of triphenyl phosphine, polymer bound [3 mmol/g loading](1.2-6.0 equiv) in DCM or PPh₃ (1.0 equiv) in DCM or THF, was added aphenol 6 (1.0 equiv) and the desired alcohol (1.0 equiv). The reactionwas then cooled to 0° C. in an ice bath and added diisopropylazodicarboxylate (DIAD) (1.0 equiv). The reaction was then allowed towarm to rt and stirred for 4-12 hours. The reaction mixture was filteredand the filtrate was concentrated under reduced pressure to give a crudeproduct, which was taken on to the next step without any furtherpurification.

General Protocol for One Pot Deprotection of Both Boc and Oxazolidine(8)

To a solution of compound 8 in DCM added TFA (10-50% v/v) and 1% anisoleor triisopropyl silane (TIPS) as scavenger. The reaction mixture wasallowed to stir at rt for 0.5-2 hours, dried under vacuum and wassubjected directly to prep HPLC purification. The product was purifiedby prep HPLC on a C8(2) column ((Luna, 5μ, 100×21.10 mm) withacetonitrile-H₂O (0.1% TFA) as mobile phase and gradient 30-98% in 20min.

(S)-2-Amino-2-(5-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol(8a)

The title compound was prepared from protected phenyl-thiadiazole 6a in90% (579 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 1.68 min with gradient 50-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=446.2; ¹H NMR (400 MHz, DMSO-d₆) δ8.21 (dd, 1H, J=9.0 Hz, J=2.0 Hz), 8.15 (d, 1H, J=2.0 Hz), 7.45 (d, 1H,J=8.4), 4.21 (t, 2H, J=6.2 Hz), 3.74-3.85 (m, 3H), 1.68-1.77 (m, 5H),1.25-1.45 (m, 12H), 0.849 (t, 3H, J=6.4).

(S)-2-Amino-2-(5-(4-(decyloxy)-3(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8b)

The title compound was prepared from protected phenyl-thiadiazole 6a in50% (208 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 1.95 min with gradient 50-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=460.2; ¹H NMR (400 MHz, DMSO-d₆) δ8.2 (d, 1H, J=8.8 Hz), 8.15 (s, 1H), 7.44 (d, 1H, J=8.8 Hz), 4.21 (t,2H, J=4.8 Hz), 3.74-3.78 (m, 3H), 1.75 (t, 3H, J=6.8 Hz), 1.65 (s, 3H),1.25-1.43 (m, 14H), 0.83-0.86 (m, 3H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol(8c)

The title compound was prepared from protected phenyl-thiadiazole 6a in20% (149 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 1.66 min with gradient 50-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=534.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (br s, 2H), 8.22 (d, 1H, J=8 Hz), 8.16 (s, 1H), 7.44-7.55 (m, 5H),4.22 (t, 2H, J=6 Hz), 3.77-3.83 (m, 3H), 2.71 (t, 2H, J=7.6 Hz),1.68-1.82 (m, 7H), 1.46-1.48 (m, 2H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(3-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8d)

The title compound was prepared from protected phenyl-thiadiazole 6a in50% (379 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 2.52 min with gradient 30-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=534.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.22 (d, 1H, J=8 Hz), 8.15 (d, 1H, J=2.0 Hz), 7.43-7.55 (m, 4H), 7.44(d, 1H, J=8.8 Hz), 4.22 (t, 2H, J=6.0 Hz), 3.75-3.80 (m, 3H), 2.70 (t,2H, J=7.6 Hz), 1.78-1.82 (m, 2H), 1.67-1.70 (m, 5H), 1.45-1.47 (m, 2H).

(S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8e)

The title compound was prepared from protected phenyl-thiadiazole 6a in40% (271 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 2.48 min with gradient 30-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=480.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.21 (d, 1H, J=9.6 Hz), 8.16 (s, 1H), 7.44 (d, 1H, J=8.8 Hz), 7.13-7.27(m, 5H), 4.21 (t, 2H, J=6.4 Hz), 3.74-3.84 (m, 3H), 2.57 (t, 2H, J=7.6Hz), 1.69-1.79 (m, 5H), 1.55-1.62 (m, 2H), 1.44-1.51 (m, 2H), 1.33-1.39(m, 2H).

(S)-2-Amino-2-(5-(4-(5-(4-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8f)

The title compound was prepared from protected phenyl-thiadiazole 6a in25% (155 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 1.92 min with gradient 40-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=484.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.19 (d, 1H, J=9.6 Hz), 8.13 (s, 1H), 7.43 (d, 1H, J=8.8 Hz), 7.19-7.22(m, 2H), 7.03-7.08 (m, 2H), 4.20 (t, 2H, J=6.0 Hz), 3.74-3.79 (m, 3H),2.57 (t, 2H, J=7.6 Hz), 1.76-1.79 (m, 2H), 1.60-1.67 (m, 5H), 1.42-1.45(m, 2H).

(S)-2-Amino-2-(5-(4-(5-(3-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8g)

The title compound was prepared from protected phenyl-thiadiazole 6a in35% (304 mg) yield. HPLC retention time on a C8(2) column (30×50 mm, 3μL) is 2.71 min with gradient 20-95% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase. MS (ESI, M+H⁺)=484.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.21 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 8.15 (s, 1H), 7.44 (d, 1H, J==8.8Hz), 7.26-7.31 (m, 1H), 6.94-7.09 (m, 3H), 4.21 (t, 2H, J=6.0 Hz),3.74-3.83 (m, 3H), 2.61 (t, 2H, J=7.6 Hz), 1.75-1.82 (m, 2H), 1.60-1.68(m, 5H), 1.38-1.48 (m, 4H).

(S)-2-Amino-2-(5-(4-((4-phenyl-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8h)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 38% (254 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.47 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=560.0; ¹H NMR (400 MHz,DMSO-d₆) δ 8.88 (br s, 2H), 8.31 (dd, 1H, J=9.2 Hz, J=2.4 Hz), 8.23 (d,1H, J=2.0 Hz), 7.44-7.51 (m, 6H), 6.11 (s, 1H), 5.72 (s, 2H), 3.79-3.85(m, 3H), 1.72 (s, 3H).

(S)-2-Amino-2-(5-(4-(7-phenylheptyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8i)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 50% (306 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.32 min with gradient 40-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=494.2; ¹H NMR (400 MHz,DMSO-d₆) δ 8.87 (br s, 2H), 8.22 (dd, 1H, J=8.8, J=2.4), 8.16 (d, 1H,J=2.0 Hz), 7.45 (d, 1H, J=8.4 Hz), 7.24-7.25 (m, 4H), 7.13-7.17 (m, 2H),7.04 (s, 1H), 4.21 (t, 2H, J=6.0 Hz), 3.78-3.85 (m, 3H), 2.56 (t. 2H,J=7.6 Hz), 1.67-1.78 (m, 4H), 1.53-1.61 (m, 2H), δ 1.27-1.47 (m, 5H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8j)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 58% (35 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 0.70 min with gradient 40-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=492.0; ¹H NMR (400 MHz,DMSO-d₆) δ 8.79 (br s, 2H), 8.22 (dd, 1H, J=9.0 Hz, J=2.0 Hz), 8.15 (d,1H, J=2.4 Hz), 7.73 (d, 1H, J=8 Hz), 7.45-7.52 (m, 4H), 4.49 (t, 2H,J=6.4 Hz), 3.75-3.85 (m, 3H), 3.28 (t, 2H, J=6.4 Hz), 1.70 (s, 3H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8k)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 51% (30.7 mg) yield. HPLC retention time on a Synergi-Max RPcolumn (2×20 mm, 2 μL) is 0.68 min with gradient 40-99% acetonitrile-H₂O(0.1% TEA) in 2 min as mobile phase. MS (ESI, M+H⁺)=491.9; ¹H NMR (400MHz, DMSO-d₆) δ 8.88 (br s, 2H), 8.21 (dd, 1H, J=8.6 Hz, J=2.0 Hz), 8.14(d, 1H, J=2.4 Hz), 7.49-7.70 (m, 5H), 4.48 (t, 2H, J=6.4 Hz), 3.77-3.85(m, 3H), 3.20 (t, 2H, J=6.0 Hz), 1.71 (s, 3H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(81)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 64% (39 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 0.77 min with gradient 50-98% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=491.9; ¹H NMR (400 MHz,DMSO-d₆) δ 8.91 (br s, 2H), 8.22 (dd, 1H, J=9.0 Hz, J=2.0 Hz), 8.15 (d,1H, J=2.4 Hz), 7.44-7.68 (m, 5H), 4.49 (t, 2H, J=6.0 Hz), 3.74-3.86 (m,3H), 3.20 (t, 2H, J=6.4 Hz), 1.71 (s, 3H).

(S)-2-Amino-2-(5-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8m)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 19% (10 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.37 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=409.9; ¹H NMR (400 MHz,CD₃OD) δ 8.25 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz),7.32-7.48 (m, 6H), 5.34 (s, 2H), 3.89-3.96 (m, 2H, 1.83 (s, 3H).

(S)-2-Amino-2-(5-(4-phenethoxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8n)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 12% (6.2 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.45 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=423.9; ¹H NMR (400 MHz,CD₃OD) δ 8.25 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz),7.26-7.35 (m, 6H), 4.40 (t, 2H, J=6.8 Hz), 3.89-3.96 (m, 2H), 3.14 (t,2H, J=6.8 Hz), 1.82 (s, 3H).

(S)-2-Amino-2-(5-(4-(3-phenylpropoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8o)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 12% (6.0 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.26 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=437.9; ¹H NMR (400 MHz,CD₃OD) δ 8.25 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz),7.16-7.31 (m, 6H), 4.16 (t, 2H, J=6.0 Hz), 3.89-3.96 (m, 2H), 2.85 (t,2H, J=7.6 Hz), 2.13-2.17 (m, 2H), 1.83 (s, 3H).

(S)-2-Amino-2-(5-(4-(benzofuran-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8p)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 29% (16 mg) yield. HPLC retention time on a C8(2) column (30×50mm, 3 μL) is 2.12 min with gradient 20-98% acetonitrile-H₂O (0.1% TFA)in 2 min as mobile phase. MS (ESI, M+H⁺)=450.0; ¹H NMR (400 MHz,DMSO-d₆) δ 8.85 (br s, 2H), 8.28 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 8.20 (d,1H, J=2.0 Hz), 7.89-7.74 (m, 3H), 7.25-7.37 (m, 2H), 6.97-7.23 (m, 1H),5.59 (s, 3H), 3.75-3.85 (m, 3H), 1.71 (s, 3H).

(S)-2-Amino-2-(5-(4-(benzo[b]thiophen-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8q)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 16% (9 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.49 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=465.9; ¹H NMR (400 MHz,DMSO-d₆) δ 8.82 (br s, 2H), 8.28 (dd, 1H, J=8.6 Hz, J=2.0 Hz), 8.19 (d,1H, J=2.4 Hz), 8.02-8.04 (m, 1H), 7.91-7.93 (m, 1H), 7.74 (d, 1H, J=8.8Hz), 7.40-7.46 (m, 2H), 6.95-7.21 (m, 1H), 5.66 (s, 2H), 3.75-3.85 (m,3H), 1.70 (s, 3H).

(S)-2-Amino-2-(5-(4-(benzo[d][1,3]dioxol-5-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8r)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 41% (232 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.38 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺) 453.9; ¹H NMR (400 MHz,DMSO-d₆) δ 8.87 (br s, 2H), 8.26 (dd, 1H, J=9.2 Hz, J=2.4 Hz), 8.19 (d,1H, J=2.4 Hz), 7.58 (d, 1H, J=8.8 Hz), 6.87-7.12 (m, 3H), 6.07 (s, 2H),5.34 (s, 2H), 3.76-3.85 (m, 2H), 1.71 (s, 3H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(3-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8s)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 29% (184 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.67 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=519.9; ¹H NMR (400 MHz,CD₃OD) δ 8.22 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.6 Hz, J=2.4 Hz), 7.56(d, 2H, J=8.4 Hz), 7.4 (d, 2H, J=8.0 Hz), 7.33 (d, 1H, J=8.8 Hz), 4.23(t, 2H, J=5.2 Hz), 3.92-4.00 (m, 2H), 2.80 (t, 2H, J=6.8 Hz), 1.88-1.92(m, 4H), 1.84 (s, 3H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8t)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 12% (7.8 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.64 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺) 519.9; ¹H NMR (400 MHz,CD₃OD) δ 8.22 (d, 1H, J=2.0 Hz), 8.16 (dd, 1H, J=8.6 Hz, J=2.0 Hz),7.46-7.51 (m, 4H), 7.34 (d, 1H, J=9.2 Hz), 4.24 (s, 2H), 3.90-3.98 (m,2H), 2.80 (t, 2H, J=6.8 Hz), 1.88-1.91 (m, 4H), 1.83 (s, 3H).

(2S)-2-Amino-2-(5-(4-(3,7-dimethyloctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8u)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 41% (19 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.79 min with gradient 50-98% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=460.0; ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.17 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 7.36(d, 1H, J=8.4 Hz), 4.86 (s, SH), 4.22-4.27 (m, 2H), 3.90-3.98 (m, 2H),1.87-1.90 (m, 1H), 1.83 (s, 3H), 1.74-1.78 (m, 1H), 1.61-1.65 (m, 1H),1.50-1.55 (m, 1H), 1.30-1.40 (m, 3H), 1.16-1.22 (m, 3H), 0.97 (d, 3H,J=6.4 Hz), 0.88 (d, 6H, J=6.8 Hz)

(S)-2-Amino-2-(5-(4-(4-propylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8v)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 47% (27 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 min, 2 μL) is 1.66 min with gradient 50-98% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺) 466.0; ¹H NMR (400 MHz,CD₃OD) δ 8.20 (d, 1H, J=1.6 Hz), 8.13 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 7.32(d, 1H, J=8.8 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.10 (d, 2H, J=8.4 Hz), 4.44(t, 2H, J=6.6 Hz), 3.90-3.98 (m, 2H), 3.10 (t, 2H, J=6.6 Hz), 2.55 (t,2H, J=7.6 Hz), 1.83 (s, 3H), 1.58-1.64 (m, 2H), 1.25 (d, 5H, J=6.4),0.91 (t, 3H, J=7.6).

(S)-2-Amino-2-(5-(4-(4-butylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8w)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 38% (23 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 min, 2 μL) is 1.73 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=479.9; ¹H NMR (400 MHz,CD₃OD) δ 8.20 (d, 1H, J=1.6 Hz), 8.13 (dd, 1H, J=2.4 Hz, J=8.8 Hz), 7.32(d, 1H, J=8.8 Hz), 7.22 (d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz), 4.36 (t,2H, J=6.4), 3.90-3.98 (m, 2H), 3.10 (t, 2H, J=6.8 Hz), 2.57 (t, 2H,J=7.6 Hz), 1.83 (s, 3H), 1.53-1.61 (m, 2H), 1.31-1.36 (m, 2H), 0.917 (t,3H, J=7.2 Hz).

(S)-2-Amino-2-(5-(4-(4-ethylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8x)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 63% (36 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.59 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=451.9; ¹H NMR (400 MHz,CD₃OD) δ 8.20 (d, 1H, J=1.6 Hz), 8.14 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 7.32(d, 1H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.12 (d, 2H, J=8.0 Hz), 4.36(t, 2H, J=6.8 Hz), 3.90-3.98 (m, 2H), 3.10 (t, 2H, J=6.8 Hz), 2.55-2.65(m, 2H), 1.83 (s, 3H), 1.20 (t, 3H, J=7.6 Hz).

(S)-2-Amino-2-(5-(4-(7,7,8,8,8-pentafluorooctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8y)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 35% (22 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.68 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=522.0; ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.6 Hz, J=2.4 Hz), 7.34(d, 1H, J=9.2 Hz), 4.21 (t, 2H, J=6.0 Hz), 3.90-3.96 (m, 2H), 2.05-2.19(m, 2H), 1.84-1.91 (m, 2H), 1.81 (s, 3H), 1.48-1.67 (m, 6H).

(S)-2-Amino-2-(5-(4-(4-(2-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8z)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 8% (5 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.59 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=469.9; ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=1.6 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.34(d, 1H, J=8.4 Hz), 7.16-7.27 (m, 2H), 6.99-7.10 (m, 2H), 4.22 (t, 2H,J=5.6 Hz), 3.90-3.97 (m, 2H), 2.74 (t, 2H, J=7.2 Hz), 1.82-1.90 (m, 4H),1.82 (s, 2H).

(S)-2-Amino-2-(5-(4-(4-(3-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8aa)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 16% (9 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.60 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=469.9; ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.34(d; 1H, J=8.4 Hz), 7.23-7.29 (m, 1H), 7.02 (d, 1H, J=5.0 Hz), 6.85-6.96(m, 2H), 4.22, (t, 2H, J=5.6 Hz), 3.91-3.97 (m, 2H), 2.70-2.74 (m, 2H),1.83-1.88 (m, 4H), 1.83 (s, 3H).

(S)-2-Amino-2-(5-(4-(4-(4-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ab)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 16% (9 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.91 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=469.9; ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.6 Hz, J=2.4 Hz), 7.34(d, 1H, J=8.0 Hz), 7.2 (m, 2H), 6.95-6.70 (m, 2H), 4.21 (t, 2H, J=5.5Hz), 3.90-3.98 (m, 2H), 2.69 (t, 2H, J=6.8 Hz), 1.83-1.86 (m, 4H), 1.82(s, 3H).

(S)-2-Amino-2-(5-(4-(6-(2-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ac)

The title compound was prepared from4-(5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)-2,2,4-trimethyoxyazolidine-3-carboxylate6a in 15% (9 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.73 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI, M+H⁺)=498.1; ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.34(d, 1H, J=8.4 Hz), 7.14-7.23 (m, 2H), 6.87-7.07 (m, 2H), 4.19 (t, 2H,J=6.0 Hz), 3.90-3.97 (m, 2H), 3.79 (s, 2H), 2.66 (t, 2H, J=8.0 Hz),1.83-1.88 (m, 1H), 1.82 (s, 3H), 1.53-1.69 (m, 3H), 1.41-1.47 (m, 2H),1.25-1.27 (m, 3H).

(S)-2-Amino-2-(5-(4-(6-(3-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ad)

The title compound was prepared from deprotected acyl-benzohydrazide 5bin 23% (11.3 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.69 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI): 497.98 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.6 Hz, J=2.4 Hz), 7.34(d, 1H, J=8.4 Hz), 7.20-7.24 (m, 1H), 6.98 (d, 1H, J=7.6 Hz), 6.85-6.91(m, 2H), 4.19 (t, 2H, J=6.4 Hz), 3.90-3.96 (m, 2H), 2.64 (t, 1H, J=7.6Hz), 1.85-2.01 (m, 2H), 1.83 (s, 3H), 1.63-1.68 (m, 2H), 1.55-1.59 (m,2H), 1.40-1.46 (m, 2H).

(S)-2-Amino-2-(5-(4-(6-(4-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ae)

The title compound was prepared from deprotected acyl-benzohydrazide 5bin 35% (17.4 mg) yield. HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.69 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase. MS (ESI): 497.98 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.0 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.32(d, 1H, J=8.4 Hz), 7.14-7.17 (m, 2H), 6.92-6.96 (m, 2H), 4.18 (t, 2H,J=6.4 Hz), 3.90-3.98 (m, 2H), 2.60 (t, 1H, J=8.0 Hz), 1.85-2.01 (m, 2H),1.83 (s, 3H), 1.60-1.68 (m, 2H), 1.52-1.58 (m, 2H), 1.38-1.44 (m, 2H).

(S)-2-Amino-2-(5-(4-(5-(3,4-difluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8af)

The title compound was prepared from deprotected acyl-benzohydrazide 5bin 44% (22.0 mg). HPLC retention time on a Synergi-Max RP column (2×20mm, 2 μL) is 1.46 min with gradient 30-99% acetonitrile-H₂O (0.1% TFA)in 2 min as mobile phase. MS (ESI): 501.86 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=2.4 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.34(d, 1H, J=8.4 Hz), 7.05-7.14 (m, 2H), 6.94-6.98 (m, 1H), 4.20 (t, 2H,J=6.0 Hz), 3.89-3.96 (m, 2H), 2.64 (t, 2H, J=7.2 Hz), 1.85-1.91 (m, 2H),1.83 (s, 3H), 1.66-1.74 (m, 2H), 1.52-1.58 (m, 2H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(2,4,5-trifluorophenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ag)

The title compound was prepared from deprotected acyl-benzohydrazide 5bin 28% (14.7 mg). HPLC retention time on a Synergi-Max RP column (2×20mm, 2 μL) is 1.69 min with gradient 20-95% acetonitrile-H₂O (0.1% TFA)in 2 min as mobile phase. MS (ES): 497.98 (MH⁺); ¹H NMR (400 MHz, CD₃OD)δ 8.21 (d, 1H, J=2 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.34 (d, 1H,J=9.2 Hz), 7.14-7.21 (m, 1H), 7.02-7.08 (m, 1H), 4.20 (t, 2H, J=6.0 Hz),3.89-3.98 (m, 2H), 2.65 (t, 2H, J=7.2 Hz), 1.83-1.90 (m, 5H), 1.65-1.71(m, 2H), 1.53-1.59 (m, 2H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(3-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ah)

The title compound was prepared from deprotected acyl-benzohydrazide 5bin 60% (33.1 mg). HPLC retention time on a Synergi-Max RP column (2×20mm, 2 μL) is 1.73 min with gradient 20-95% acetonitrile-H₂O (0.1% TFA)in 2 min as mobile phase. MS (ESI): 548.00 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 8.21 (d, 1H, J=1.6 Hz), 8.16 (dd, 1H, J=8.4 Hz, J=2.4 Hz),7.44-7.46 (m, 4H), 7.33 (d, 1H, J=8.4 Hz), 4.19 (t, 2H, J=6.4 Hz),3.90-3.99 (m, 2H), 2.71 (t, 2H, J=7.6 Hz), 1.81-1.88 (m, 2H), 1.65-1.73(m, 2H), 1.54-1.61 (m, 2H), 1.39-1.47 (m, 2H), 1.24-1.28 (m, 3H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(4-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(8ai)

The title compound was prepared from deprotected acyl-benzohydrazide 5bin 59% (32.0 mg). HPLC retention time on a Synergi-Max RP column (2×20mm, 2 μL) is 1.74 min with gradient 20-95% acetonitrile-H₂O (0.1% TFA)in 2 min as mobile phase. MS (ESI): 547.92 (MH⁺); ¹H NMR (400 MHz,CD₃OD) δ 8.22 (d, 1H, J=2.0 Hz), 8.16 (dd, 1H, J=8.6 Hz, J=2.0 Hz), 7.53(d, 2H, J=8.0 Hz), 7.32-7.37 (m, 3H), 4.19 (t, 2H, J=6.4 Hz), 3.90-3.98(m, 2H), 2.72 (t, 2H, J=7.6 Hz), 1.81-1.88 (m, 2H), 1.66-1.73 (m, 2H),1.54-1.61 (m, 2H), 1.41-1.47 (m, 2H), 1.24-1.27 (m, 3H).

General Approach to Synthesis of Thio-Ether-Phenyl-Thiadiazoles

Synthesis of thio-ether-phenyl-thiazoles is described in Scheme 5.Treatment of substituted 4-fluorobenzoic acid 1 with TMS-CHN₂ affordedcorresponding methyl ester with upon reaction with various thiolsafforded the substituted thio-ether 2. The substituted thio-ether 2 wasthen condensed with hydrazine to afford benzohydrazide 3. Reaction ofbenzohydrazide 3 with orthogonally protected amino acid 4 under HATUconditions to give acyl-benzohydrazide 5 which upon treatment withLawesson's reagent provided phenol 6 in good yield. Mitsunobu reactionof phenol 6 with desired alcohol followed by deprotection afforded thedesired final compound 7. Acyl-benzohydrazide 5 could also be oxidizedwith mCPBA to afford acyl-benzohydrazide 8 before treatment withLawesson's reagent and deprotection. Reaction of the alcohol 7 withdiethyl chlorophosphate followed by deprotection with TMSBr gave thecorresponding phosphate.

4-(Octylthio)-3-(trifluoromethyl)benzohydrazide (3a)

To a solution of 4-fluoro-3-(trifluoromethyl)benzoic acid 1a (1.04 g, 5mmol) in DCM/MeOH (4:1, 10 mL) at 0° C. was added drop-wise a solutionof TMSCHN₂ (2.0 M in ether, 2.6 mL, 5.1 mmol). The reaction mixture wasstirred at 0° C. until the colorless solution started to turn lightyellow and maintained its light yellow color. The reaction was stirredfor an additional 20 minutes then a few drops of acetic acid was addedto quench the last few drops of TMS-CHN₂ (the solution turns colorlessfrom light yellow). The solvent was removed in vacuo to give a crudeproduct which was used directly for next step. MS (ESI, M+H⁺)=223.0

To a solution of the crude methyl ester in DMF (5 mL) was addedoctane-1-thiol (0.87 mL, 5 mmol) and Cs₂CO₃ (2.44 g, 7.5 mmol). Thereaction mixture was stirred at 60° C. for 1 h, concentrated, quenchedwith NH₄Cl, extracted with EtOAc. The organics was dried over Na₂SO₄,concentrated under reduced pressure to leave the crude methyl4-(octylthio)-3-(trifluoromethyl)benzoate 2a. MS (ESI, M+H⁺)=349.0

The crude methyl 4-(octylthio)-3-(trifluoromethyl)benzoate was dissolvedin 2 mL of MeOH and treated with 2 mL of hydrazine hydrate. The reactionmixture was left to stir at 80° C. for 1 hour, poured into ice-water.The solid was filtered, washed with H₂O and dried under vacuum toprovide the 4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a as ayellow solid. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was2.69 min with gradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min asmobile phase. MS (ESI, M+H⁺)=349.3; ¹H NMR (400 MHz, CDCl₃) δ 9.99 (s,1H), 8.13 (d, 1H, J=1.6 Hz), 8.03 (dd, 1H, J=8.2 Hz, J=1.6 Hz), 7.67 (d,1H, J=8.8 Hz), 4.59 (s, 2H), 3.13 (t, 2H, J=7.2 Hz), 1.61 pentet, 2H,J=6.8 Hz), 1.44-1.36 (m, 2H), 1.30-1.20 (m, 8H), 0.85 (t, 3H, J=6.8 Hz).

(R)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(octylthio)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate (5a)

To a solution of(R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid4 (129.6 mg, 0.5 mmol) in DMF (1 mL) was added HATU (209 mg, 0.55 mol)and DIPEA (0.436 mL, 2.5 mmol). After being stirred at rt for 10 min,the reaction mixture was treated with4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a (174 mg, 0.5 mmol) inTHF (2 mL) and was left stirred overnight. Aqueous NaHCO₃ solution wasadded and the mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and evaporated underreduced pressure to give a residue, which was purified by SiO₂ columnchromatograph (n-hexane/EtOAc=3:7) to give (R)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octylthio)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate5a (247 mg, 84%). HPLC retention time on a C18 column (30×4.6 mm, 3.5μ)was 3.08 min with gradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 minas mobile phase. MS (ESI, M+H⁺)=590.5

(S)-2-Amino-2-(5-(4-(octylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(7a)

The title product was obtained in 32% yield from (R)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octylthio)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate6a. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.46 minwith gradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobilephase. MS (ESI, M+H⁺)=448.4. ¹H NMR (400 MHz, CD₃OD) δ 8.17 (s, 1H),8.13 (d, 1H, J=8.4 Hz), 7.75 (d, 1H, J=8.4 Hz), 3.80 (AB, 1H,J_(AB)=11.2 Hz), 3.73 (AB, 1H, J_(AB)=11.2 Hz), 3.14 (t, 2H, J=7.2 Hz),1.67 (s, 3H), 1.61 (pentet, 2H, J=6.8 Hz), 1.40-1.35 (m, 2H), 1.25-1.20(m, 8H), 0.81 (t, 3H, J=6.6 Hz).

(R)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(octylsulfonyl)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate (8a)

A solution of (R)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octylthio)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate5a (123 mg, 0.21 mmol) in DCM (10 mL) was treated with mCPBA (164 mg,77%, 722 mmol) at rt. The reaction mixture was stirred at rt overnight,quenched with saturated aqueous NaHCO₃, extracted with DCM. The organiclayer was washed with saturated aqueous NaHCO₃ (3×), dried over Na₂SO₄,and evaporated under reduced pressure to give a residue, which waspurified by SiO₂ column chromatograph (n-hexane/EtOAc=3:7) to leave(R)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octylsulfonyl)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate8a (112 mg, 92%). HPLC retention time on a C18 column (30×4.6 mm, 3.5μ)was 3.27 min with gradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 minas mobile phase. MS (ESI, M+H⁺)=622.5.

(S)-2-Amino-2-(5-(4-(octylsulfonyl)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(7b)

The title compound was prepared according to general procedure from(R)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octylsulfonyl)-3-(trifluoromethyl)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate 8a. HPLC retention time on a C18 column(30×4.6 mm, 3.5μ) was 2.11 min with gradient 10-95% acetonitrile-H₂O(0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H⁺)=480.3; ¹H NMR (400MHz, DMSO-d₆) δ 8.56 (dd, 1H, J=8.2 Hz, J=1.6 Hz), 8.53 (d, 1H, J=1.6Hz), 8.38 (d, 1H, J=8.8 Hz), 3.87 (AB, 1H, J_(AB)=10.8 Hz), 3.80 (AB,1H, J_(AB)=10.8 Hz), 3.44 (t, 1H, J=7.8 Hz), 1.68 (s, 3H), 1.66-1.60 (m,2H), 1.37-1.31 (m, 2H), 1.25-1.16 (m, 8H), 0.83 (t, 3H, J=7.2 Hz).

General Approach to Synthesis of Phenyl-Oxadiazoles

Synthesis of phenyl-oxadiazoles is described in Scheme 6. Reaction ofthe desired alcohol with substituted 4-fluorobenzonitrile 1 afforded thesubstituted benzonitrile 2. The substituted benzonitrile 2 was thencondensed with hydroxylamine to afford hydroxybenzimidamide 3. Couplingof the hydroxyamindine intermediate 3 with orthogonally protected aminoacid 4 under HATU conditions followed by cyclization providedorthogonally protected oxadiazole 6. Treatment of protected oxadiazole 6with TFA gave the desired final amino-alcohol 7.

4-(Octyloxy)-3-(trifluoromethyl)benzonitrile (2a)

The title compound was prepared analogously to compound 2 (Scheme 4)in >95% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, 1H, J=0.2 Hz), 7.77(dd, 1H, J=8.8 Hz, J=2.0 Hz), 7.04 (d, 1H, J=8.8 Hz), 4.11 (t, 2H, J=5.6Hz), 1.84 (m, 2H), 1.47 (m, 2H), 1.32 (m, 8H), 0.89 (t, 3H, J=7.2 Hz).

(R)-tert-Butyl2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)oxazolidine-3-carboxylate(6a)

A suspension of 4-(octyloxy)-3-(trifluoromethyl)benzonitrile (600 mg, 10equiv), NH₂OH.HCl (280 mg, 2.0 equiv), Na₂CO₃ (636 mg, 3.0 equiv) inethanol-water (12 mL, 5:1) was refluxed for 3 h. The reaction wascondensed under vacuum and the residue was treated with water followedby extraction with ethyl acetate. The ethyl acetate layer was washedwith saturated NaCl (1×), dried over Na₂SO₄, and condensed to affordhydroxyamindine intermediate (750 mg). Part of the intermediate (166 mg,1.0 equiv) was treated with HATU (190 mg, 1.0 equiv), DIEA (260 μL, 3.0equiv) and(R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(130 mg, 1.0 equiv) in DMF (1 mL) for 1 hour. The reaction was dilutedwith ethyl acetate and washed with water followed by saturated NaCl(1×), dried over Na₂SO₄, and condensed under vacuum. The residue wasdissolved in DMF and heated at 120° C. for 2 hours. Aqueous workupfollowed by Isco system purification provided the title compound in 28%(70 mg) yield over three steps. MS (ESI, M+H⁺)=558.1 ¹H NMR (400 MHz,CDCl₃) δ 8.28 (d, 1H, J=1.6 Hz), 8.18 (dd, 1H, J=8.4 Hz, J=1.6 Hz), 7.07(d, 1H, J=8.4 Hz), 4.23, 4.00 (AB, 2H, J=9.2 Hz), 4.11 (t, 2H, J=7.2Hz), 1.92 (s, 3H), 1.84 (m, 2H), 1.76 (s, 3H), 1.70 (s, 3H), 1.51-1.46(m, 4H), 1.25 (m, 9H), 1.25 (s, 6H), 0.89 (t, 3H, J=7.2 Hz).

(S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol(7a)

The title compound was prepared analogously to compound 8 (Scheme 4)from compound 7a. MS (ESI, M+H⁺)=416.0; ¹H NMR (400 MHz, CD₃OD) δ 8.28(m, 2H), 7.34 (d, 1H, J=9.6 Hz), 4.19 (t, 2H, J=5.6 Hz), 4.11, 3.89 (AB,2H, J=11.6 Hz), 1.84 (m, 2H), 1.77 (s, 3H), 1.53 (m, 2H), 1.40-1.32 (m,8H), 0.91 (t, 3H, J=7.2 Hz).

General Approach to Synthesis of Phenyl-Isoxazoles and Phenyl-Pyrazoles

Synthesis of phenyl-isoxazoles and phenyl-pyrazoles are described inScheme 7.

Reaction of the desired benzoic acid with oxalyl chloride and trappingthe acid chloride with enolate of oxazolidine-ketone 2 afforded1,3-dione 3. Oxazolidine-ketone 2 was synthesized fromoxazolidine-carboxylate 8 after conversion of 8 to corresponding Weinrebamide followed by addition of methyl lithium. Reaction of the 1,3-dione3 with either hydrazine or hydroxylamine followed by deprotectionafforded the desired final compound 6 and 7 respectively.

(R)-tert-Butyl 4-acetyl-2,2,4-trimethyloxazolidine-3-carboxylate (2)

To a solution of(R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid8 (2.6 g, 10 mmol, 1.0 equiv) in DMF (25 mL) was added HATU (4.6 g, 12mmol, 1.2 equiv) and DIPEA (8.7 mL, 50 mmol, 5.0 equiv). The reactionmixture was stirred at rt for 10 min and treated withN,O-dimethylhydroxylamine hydrochloride (2.9 g, 30 mmol, 3.0 equiv),stirred for 2 days at rt, quenched with half saturated NaHCO₃, extractedwith EtOAc. The organics was dried over Na₂SO₄, concentrated to affordcorresponding Weinreb amide in 92% (2.78 g) yield. HPLC retention timeon a C18 column (30×4.6 mm, 3.5μ) was 2.20 min with gradient 10-95%acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI,M+H⁺)=303.3.

The crude corresponding Weinreb amide (2.78 g, 9.2 mmol, 1.0 equiv) wasdissolved in THF (50 mL), cooled to −78° C. and treated with a solutionof 1.6 M MeLi (14.7 mL, 23 mmol, 2.5 equiv) in ether drop-wise. Afterbeing stirred at −78° C. for 3 h, the reaction mixture was allowed towarm to rt, quenched with saturated aqueous NH₄Cl, extracted with EtOAc.The organics was dried over Na₂SO₄, concentrated in vacuo to afforded anoil which was purified by silica gel column chromatograph(n-hexane/EtOAc=85:15) to give (R)-tert-butyl4-acetyl-2,2,4-trimethyloxazolidine-3-carboxylate as a white solid in82% (1.94 g) yield. HPLC retention time on a C18 column (30×4.6 mm,3.5μ) was 2.39 min with gradient 10-95% acetonitrile-H₂O (0.1% TFA) in3.5 min as mobile phase. MS (ESI, M+H⁺)=258.4; ¹H NMR (400 MHz, CDCl₃) δ3.95 (d, 1H, J=9.6 Hz), 3.74 (d, 1H, J=9.6 Hz), 2.21 (s, 3H), 1.69 (s,2H), 1.65-1.64 (m, 1H), 1.61 (s, 2H), 1.57-1.55 (m, 2H), 1.49 (s, 5H),1.42 (s, 6H).

(S)-tert-Butyl2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-3-oxo-propanoyl)oxazolidine-3-carboxylate(3a)

4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (460 mg, 1.0 equiv) wastreated with oxalyl chloride (244 μL, 2.0 equiv) for 30 min. Thereaction was condensed and part of the reside (81 mg, 1.2 equiv) wasdissolved in THF and transferred to a solution of (S)-tert-butyl4-acetyl-2,2,4-trimethyloxazolidine-3-carboxylate (51 mg, 1.0 equiv) and11.0M LiHMDS (0.72 mL, 3.0 equiv) in THF at −78° C. The resultant wasstirred at 0° C. for 1 hour. The reaction was quenched with aqueousNH₄Cl and extracted with ethyl acetate. The organic layer was washedwith brine and dried over Na₂SO₄ and condensed in vacuo. The residue waspurified on a silica gel column with ethyl acetate-hexane (0-30%) aseluent system to afford the title compound in 39% (55 mg) yield. MS(ESI, M+H⁺)=557.9

(R)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-1-ol(6a)

The solution of (S)-tert-butyl2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-3-oxo-propanoyl)oxazolidine-3-carboxylate(27 mg, 0.05 mmol, 1.0 equiv) and hydrazine monohydrate (2.7 μL, 0.055mmol, 1.1 equiv) in methanol (0.2 mL) was stirred at room temperaturefor 2 hours. The reaction was condensed and the residue was treated with20% TFA-DCM for 30 min. After removal of excess amount of TFA and DCM,the crude product was purified by prep. HPLC and afforded the titlecompound as mono-TFA salt (5.0 mg). MS (ESI, M+H⁺)=414.0; ¹H NMR (400MHz, CD₃OD) δ 7.81 (s, 1H), 7.76 (d, 1H, J=9.2 Hz), 7.14 (d, 1H, J=9.2Hz), 6.56 (s, 1H), 4.03 (t, 2H, J=6.0 Hz), 3.79, 3.67 (AB, 2H, J=12.0Hz), 1.76-1.69 (m, 2H), 1.59 (s, 3H), 1.46-1.38 (m, 2H), 1.32-1.16 (m,8H), 0.81 (t, 3H, J=7.2 Hz).

(S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-1-ol(7a)

The solution of (S)-tert-butyl2,2,4-trimethyl-4-(3-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-3-oxo-propanoyl)oxazolidine-3-carboxylate(27 mg, 0.05 mmol, 1.0 equiv) and hydroxylamine hydrochloride (6.6 mg,0.10 mmol, 2.0 equiv) in pyridine (0.5 mL) was stirred at 60° C. for 2days. The reaction was condensed and the residue was treated with 20%TFA-DCM for 30 min. After removal of excess amount of TFA and DCM, thecrude product was purified by prep. HPLC and afforded the title compoundas mono-TFA salt (6.0 mg). MS (ESI, M+H⁺)=415.0; ¹H NMR (400 MHz, CD₃OD)δ 8.06 (s, 1H), 8.04 (d, 1H, J=9.6 Hz), 7.31 (d, 1H, J=9.6 Hz), 7.03 (s,1H), 4.16 (t, 2H, J=6.0 Hz), 4.01, 3.83 (AB, 2H, J=12.0 Hz), 1.87-1.80(m, 2H), 1.75 (s, 3H), 1.56-1.47 (m, 2H), 1.40-1.32 (m, 8H), 0.91 (t,3H, J=7.2 Hz).

General Approach to Synthesis of Phenyl-Pyridine Analogs

Synthesis of phenyl-pyridine analogs is described in Scheme 8. Reactionof desired alcohol with substituted halo-benzene 1 afforded thehalo-benzene-ether 2. The substituted halo-benzene-ether 2 was thentreated with n-butyl lithium, B(OMe)₃, and pinacol respectively toafford ester 3. Suzuki cross-coupling of ester 3 with compound 4 gavebiaryl 5 which upon reduction and deprotection afforded amino alcohol 6.

4-Bromo-1-(octyloxy)-2-(trifluoromethyl)benzene (2a)

Using 4-bromo-1-fluoro-2-(trifluoromethyl)benzene as starting material,standard aromatic fluoro-substitution with n-octanol provided the titlecompound in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (δ, 1H,J=2.4 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.85 (d, 1H, J=8.8 Hz),4.01 (t, 2H, J=6.4 Hz), 1.80 (m, 2H), 1.46 (m, 2H), 1.32 (m, 8H), 0.90(t, 2H, J=5.6 Hz).

4,4,5,5-Tetramethyl-2-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane(3a)

Using 4-bromo-1-(octyloxy)-2-(trifluoromethyl)benzene as startingmaterial, the title compound was prepared using a literature procedurein 96% yield (J. Am. Chem. Soc. 2004, 126, 14316-14317). ¹H NMR (400MHz, CDCl₃) δ 7.99 (s, 1H), 7.89 (dd, 1H, J=8.4 Hz, J=1.2 Hz), 6.95 (d,1H, J=8.4 Hz), 4.06 (t, 2H, J=6.0 Hz), 1.81 (m, 2H), 1.47 (m, 2H),1.36-1.28 (m, 8H), 0.88 (t, 2H, J=7.2 Hz).

Diethyl2-(tert-butoxycarbonylamino)-2-(5-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)pyridin-2-yl)malonate(5a)

The suspension of4,4,5,5-tetramethyl-2-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane3a (136 mg, 0.34 mmol, 1.5 equiv), diethyl2-(5-bromopyridin-2-yl)-2-(tert-butoxycarbonylamino)malonate (98 mg,0.23 mmol, 1.0 equiv), Pd(PPh₃)₄ (26.3 mg, 0.023 mmol, 0.1 equiv), andNa₂CO₃ (120 mg, 1.14 mmol, 4.0 equiv) in ethanol-H₂O was heated at 80°C. for 1 hour. The reaction mixture was filtered and the filtrate waspurified by silica gel column to afford the title compound in 77% (110mg) yield. MS (ESI, M+H⁺)=625.1; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H),7.88 (s, 1H), 7.86 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.75 (d, J=2.5 Hz),7.66 (d, 1H, J=8.4 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.82 (s, 1H), 4.30 (m,4H), 4.09 (t, 2H, J=6.0 Hz), 1.84 (m, 2H), 1.46 (m, 11H), 1.28 (m, 14H),0.90 (t, 3H, J=7.2 Hz).

2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)ethanol(6a)

Diethyl2-(tert-butoxycarbonylamino)-2-(5-(4-(octyloxy)-3-(trifluoromethyl)-phenyl)-pyridin-2-yl)malonate5a (110 mg, 0.176 mmol, 1.0 equiv) in THF (2.0 mL) was added LiBH₄ (57mg, 2.64 mmol, 15.0 equiv) at 0° C., followed by addition of ethanol(0.8 mL) carefully. The resultant was warmed up to room temperature for10 minutes. LC-MS indicated the completion of the reaction. The reactionwas terminated by addition of water. Extraction with ethyl acetate andthe organic layer was washed with brine and dried over sodium sulfateand condensed. The residue (crude reduction product with significantdecarboxylation) was treated with 2M HCl in THF to afford the titlecompound after preparative HPLC purification. MS (ESI, M+H⁺)=411.1; ¹HNMR (400 MHz, DMSO-d₆) δ 8.95 (d, 1H, J=2.4 Hz), 8.39 (s, 3H), 8.22 (dd,1H, J=8.4 Hz, J=2.4 Hz), 8.01 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.93 (d, 1H,J=2.0 Hz), 7.60 (d, 1H, J=8.4 Hz), 7.39 (d, 1H, J=9.2 Hz), 5.48 (br,1H), 4.48 (br, 1H), 4.17 (t, 2H, J=6.0 Hz), 3.86-3.72 (m, 2H), 1.75 (m,2H), 1.44 (m, 2H), 1.29 (m, 8H), 0.86 (t, 3H, J=6.8 Hz).

(R)-t-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadi-azol-2-yl)oxazolidine-3-carboxylate

The title compound was prepared from(S)-t-butyl-2,2,4-trimethyl-4-(2-(4-(octyloxy)benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylateusing published procedure (Tet. Letters, 2006, 47, 105-108) in 85%yield. MS (ESI, M+H⁺)=556.1; ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, 1H,J=1.6 Hz), 8.14 (d, 1H, J=8.8 Hz), 8.10 (dd, 1H, J=8.8 Hz, J=1.6 Hz),4.22 (d, 1H, J=8.8 Hz), 4.12 (t, 2H, J=6.0 Hz), 4.01 (m, 1H), 1.94 (s,3H), 1.85 (m, 2H), 1.76 (s, 3H), 1.72 (s, 3H), 1.51-1.46 (m, 4H), 1.22(m, 7H), 1.25 (s, 6H), 0.89 (t, 3H, J=7.2 Hz).

(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propan-1-ol

Standard 20% TFA deprotection of (R)-t-butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadi-azol-2-yl)oxazolidine-3-carboxylateafforded the title compound in 55% yield. (ESI, M+H⁺)=416.0; ¹H NMR (400MHz, CD₃OD) δ 8.18 (d, 1H, J=8.8 Hz), 8.18 (s, 1H), 7.30 (d, 1H, J=8.8Hz), 4.12 (t, 2H, J=6.0 Hz), 4.01, 3.79 (AB, 2H, J=11.6 Hz), 1.74 (m,2H), 1.68 (s, 3H), 1.43 (m, 2H), 1.31-1.19 (m, 8H), 0.81 (t, 3H, J=2.8Hz).

General Approach to Synthesis of Ether-Phenyl-Thiazoles

The synthesis of 2,5-substituted thiazoles is described in Scheme 9.Reaction of the desired alcohol para-methoxybenzyl alcohol (PMB-OH) withsubstituted 4-fluoroacetophenone 1 afforded the acetophenoneintermediate 2. Acetophenone intermediate 2 was then converted to thecorresponding bromo-acetophenone using Bu₄NBr₃ which, upon reaction withNaN₃, provided the azido-acetophenone intermediate. Hydrogenation of theazido-acetophenone intermediate afforded amine 3, followed by couplingwith orthogonally protected amino acid 4 gave amide 5. Removal of PMBgroup under hydrogenation gave phenol 6. Mitsunobu reaction of thephenol 6 with the desired alcohol followed by thiazole formation underLawesson's reagent conditions afforded intermediate 7 in good yield.Removal of the protecting group from intermediate 7 afforded the finalamino-alcohol 8.

For general protocol for synthesis of compound 2, 3, 4, and 5 refer toscheme 1.

1-(4-(4-Methoxybenzyloxy)-3-(trifluoromethyl)phenyl)ethanone (2a)

For general protocol for synthesis of compound 2 refer to scheme 1. Theproduct was purified by silica gel column chromatography using theCombi-Flash system (Hex:EtOAc) as colorless oil in 90% (4.25 g). HPLCretention time on a C8(2) column (30×3.00 mm, 3 μL) is 2.02 min withgradient 50-98% acetonitrile-H₂O (0.1% TFA) in 4.0 min as mobile phase.TLC (1:3 EtOAc:Hex), R_(f)=0.4; ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, 1H,J=1.6 Hz), 8.09 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 7.35 (d, 2H, J=8.4 Hz),7.09 (d, 1H, J=8.4 Hz), 6.93 (d, 2H, J=8.4 Hz), 5.21 (s, 2H), 3.82 (s,3H), 2.58 (s, 3H).

2-Azido-1-(4-(4-methoxybenzyloxy)-3-(trifluoromethyl)phenyl)ethanone

For general protocol for synthesis of azido intermediate refer toscheme 1. The product was purified by silica gel column chromatographyusing the Combi-Flash system (Hex:EtOAc) as yellow solid in 76% (3.64 g)yield from acetophenone 2a. HPLC retention time on a C8(2) column(30×3.00 mm, 3μ) is 2.20 min with gradient 50-98% acetonitrile-H₂O (0.1%TFA) in 4.0 min as mobile phase. TLC (1:3 EtOAc:Hex), R_(f)=0.3; ¹H NMR(400 MHz, CDCl₃) δ 8.15 (d, 1H, J=2.0 Hz), 8.05 (dd, 1H, J=8.8 Hz, J=2.4Hz), 7.33-7.36 (m, 2H), 7.12 (d, 1H, J=8.8 Hz), 6.90-6.94 (m, 2H), 5.22(s, 2H), 4.51 (s, 2H), 3.82 (s, 3H).

(R)-tert-Butyl4-(2-(4-(4-methoxybenzyloxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate(5a)

For general protocol for synthesis of compound 5 refer to scheme 1. Thereaction was stirred at room temperature for 2 hours. The product waspurified by silica gel column chromatography using the Combi-Flashsystem (Hex:EtOAc) as yellow foam in 72% (2.44 g) yield fromamino-acetophenone 3a. HPLC retention time on a C8(2) column (30×3.00mm, 3μ) is 2.51 min with gradient 50-98% acetonitrile-H₂O (0.1% TFA) in4.0 min as mobile phase. TLC (1:1 EtOAc:Hex), R_(f)=0.5; ¹H NMR (400MHz, CDCl₃) δ 8.24 (br s, 1H), 8.09 (br d, 1H, J=8.4 Hz), 7.32-7.39 (m,2H), 7.12 (d, 1H, J=8.4 Hz), 6.90-6.97 (m, 2H), 5.22 (s, 2H), 4.70 (t,2H, J=5.2 Hz), 4.30 (br S, 1H), 3.78-3.86 (m, 5H), 1.38-1.85 (m, 18H).

(R)-tert-Butyl4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate(6a)

To a solution of (R)-tert-butyl4-(2-(4-(4-methoxybenzyloxy)-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate(4) (2.4 g, 4.1 mmol, 1.0 equiv) in methanol (20 mL) was added 10% Pd/C(240 mg). The reaction mixture was stirred for 3 hours at rt under H₂atmosphere using a H₂ balloon, filtered through celite and concentratedto give (R)-tert-butyl4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate(6a) as a white foam in quantitative yield. HPLC retention time on a C18column (30×4.6 mm, 3.5μ) was 2.62 min with gradient 10-95%acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H⁺)461.4.

(R)-tert-Butyl2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate

To a solution of (R)-tert-butyl4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate(114 mg, 0.25 mmol, 1.0 equiv) and 6-phenylhexan-1-ol (45 mg, 0.25 mmol,1.0 equiv) in DCM (1 mL) was added polymer bond PPh₃ (125 mg, 0.75 mmol,3.0 equiv). The reaction mixture was stirred at rt for 0.5 hour andcooled to 0° C. A solution of DIAD (0.053 mL, 0.25 mmol, 1.0 equiv) inDCM (0.5 mL) was added drop wise to the reaction mixture. The reactionmixture was stirred at rt for 2 hours, filtered and evaporated underreduced pressure to give a residue, which was purified by SiO₂ columnchromatograph (30-50% EtOAc in hexanes) to give (R)-tert-butyl2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylatein 75% (155 mg) yield. HPLC retention time on a C18 column (30×4.6 mm,3.5μ) was 3.31 min with gradient 50-95% acetonitrile-H₂O (0.1% TFA) in3.5 min as mobile phase. MS (ESI, M+H⁺)=621.6.

(R)-tert-Butyl2,2,4-trimethyl-4-(2-oxo-2-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate

The title compound was prepared from (R)-tert-butyl4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate(0.25 mmol, 1.0 equiv) and 5-(4-(trifluoromethyl)phenyl)pentan-1-ol(0.25 mmol, 1.0 equiv) according to the general procedure in 31% yield.HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 3.26 min withgradient 50-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺)=675.6.

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(7a)

To a solution of (R)-tert-butyl2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate(49 mg, 0.079 mmol, 1.0 equiv) in toluene (1 mL) was added Lawesson'sreagent (32 mg, 0.087 mmol, 1.1 equiv). The reaction mixture was heatedat 80° C. for 3 h. The crude product was purified directly by SiO₂column chromatograph (EtOAc/hexanes, 3:7) to give (R)-tert-butyl2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate.HPLC retention time on a C8(2) column (30×50 mm, 3μ) is 3.29 min withgradient 70-98% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺)=619.0.

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(7b)

The title compound was prepared from (R)-tert-butyl2,2,4-trimethyl-4-(2-oxo-2-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)ethylcarbamoyl)-oxazolidine-3-carboxylate.HPLC retention time on a C8(2) column (30×50 mm, 3) is 3.29 min withgradient 70-98% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺)=673.0.

(S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol(8a)

The title compound was prepared from (R)-tert-butyl2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate.HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.41 min withgradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺)=479.4; ¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 1H), 7.65 (d,1H, J=2.0 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 7.28-7.23 (m, 2H),7.18-7.15 (m, 3H), 6.96 (d, 1H, J=9.2 Hz), 4.06-3.99 (m, 4H), 2.62 (t,2H, J=7.6 Hz), 1.85-1.78 (m, 5H), 1.69-1.62 (m, 2H), 1.56-1.50 (m, 2H),1.44-1.38 (m, 2H).

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)propan-1-ol(8b)

The title compound was prepared from (R)-tert-butyl2,2,4-trimethyl-4-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate.HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.50 min withgradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺)=533.4; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.66 (d,1H, J=2.0 Hz), 7.56 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.52 (d, 2H, J=8.0Hz), 7.28 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=8.8 Hz), 4.07-4.03 (m, 4H),2.70 (t, 2H, J=7.8 Hz), 1.89-1.82 (m, 5H), 1.74-1.67 (m, 2H), 1.57-1.50(m, 2H).

General Method for Phosphate Synthesis

Synthetic strategy for synthesis of desired phosphates is illustratedabove. To a solution of unprotected amino alcohol (1.0 equiv) in dryCH₂Cl₂ at RT was added excess diethyl chlorophosphate (10.0 equiv) andtriethylamine (20.0 equiv) and the reaction stirred for 12-18 hours. Thereaction was monitored by LC-MS. The crude reaction mixture was thenevaporated to dryness in vacuo. The obtained phospho-diesterintermediate was reacted with excess bromotrimethylsilane (10.0-20.0equiv) in dry CH₂Cl₂ at RT over a period of 6-10 hours to afford thefinal phosphate which was purified by reverse-phase preparative HPLCafter evaporation of the solvent and excess reagent.

(S)-2-Amino-2-(5-(4-(octylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (a)

MS (ESI, M+H⁺)=528.0; HPLC retention time on a C8(2) column (30×3.00 mm,3μ) is 2.27 min with gradient 30-98% acetonitrile-H₂O (0.1% TFA) in 3.5min as mobile phase.

(S)-2-Amino-2-(5-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (b)

MS (ESI, M+H⁺)=526.0; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.51 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(3-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (c)

MS (ESI, M+H⁺)=614.0; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.44 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (d)

MS (ESI, M+H⁺)=614.0; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.44 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-((4-phenyl-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (e)

MS (ESI, M+H⁺)=639.8; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.37 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (f)

MS (ESI, M+H⁺)=599.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.41 min with gradient 30-99% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(5-(3-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (g)

MS (ESI, M+H⁺)=563.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.53 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(5-(4-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (h)

MS (ESI, M+H⁺)=593.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.57 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(3-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (i)

MS (ESI, M+H⁺)=599.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 2.03 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(4-(4-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (j)

MS (ESI, M+H)=549.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.51 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(6-(3-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (k)

MS (ESI, M+H⁺) 577.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.65 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(6-(4-fluorophenyl)hexyloxy)-3-(trifluoromethylphenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (l)

MS (ESI, M+H⁺)=578.0; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.63 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(4-(5-(3,4-difluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (m)

MS (ESI, M+H⁺)=582.0; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.58 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(2,4,5-trifluorophenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (n)

MS (ESI, M+H⁺)=599.9; HPLC retention time on a Synergi-Max RP column(2×20 mm, 2 μL) is 1.59 min with gradient 20-95% acetonitrile-H₂O (0.1%TFA) in 2 min as mobile phase.

(S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propyldihydrogen phosphate (o)

The title product was obtained according to general procedure fromcompound 7a (Scheme 6). MS (ESI, M+H⁺)=496.0

(R)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)propyldihydrogen phosphate (p)

The title product was obtained according to general procedure fromcompound 3a (Scheme 7). MS (ESI, M+H⁺)=494.1

(S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)isoxazol-5-yl)propyldihydrogen phosphate (q)

The title product was obtained according to general procedure fromcompound 3a (Scheme 7). MS (ESI, M+H⁺)=495.0

(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propyldihydrogen phosphate (q)

The title product was obtained according to general procedure from thecorresponding amino-alcohol. MS (ESI, M+H⁺)=496.0

(S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyldihydrogen phosphate (r)

The title compound was prepared from(S)-2-amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol.HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.48 min withgradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺) 559.5.

(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)propyldihydrogen phosphate (s)

The title compound was prepared from(S)-2-amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)propan-1-ol.HPLC retention time on a C18 column (30×4.6 mm, 3.5μ was 2.53 min withgradient 10-95% acetonitrile-H₂O (0.1% TFA) in 3.5 min as mobile phase.MS (ESI, M+H⁺)=613.5.

Examples of specific methods used to make(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-oland(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-olDescription 1 1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (D1)

1-octanol (2 mL), 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (2.62g), potassium tert-butoxide (14 mL, 1.0M) and tetrahydrofuran (30 mL)were heated at 65° C. for 3 hrs to produce the title product as abrownish oil (4.00 g). The product was purified by silica gel columnchromatography using the Combi-Flash system (Hex:EtOAc) as white solidin 60% (1.20 g). TLC (1:5 EtOAc:Hex), R_(f)=0.4; ¹H NMR (400 MHz, CDCl₃)δ 8.18 (d, 1H, J=2.0 Hz), 8.10 (dd, 1H, J=8.8 Hz, J=2.3 Hz), 7.02 (d,1H, J=8.8 Hz), 4.12 (t, 2H, J=6.4 Hz), 2.58 (m, 3H), 1.80-1.89 (m, 2H),1.42-1.54 (m, 2H), 1.22-1.40 (m, 8H), 0.89 (t, 3H, J=6.7 Hz).

Description 1 Alternative Method (D1A)1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (D1)

A solution of n-octanol (13.3 g, 0.102 mol), in THF (224 mL) was treatedwith 1.0 M potassium t-butoxide in THF (112 mL, 1.1 equiv) at roomtemperature and heated to 65° C. After 15 minutes, a solution of1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21 g, 1.0 equiv) in THF(224 mL) was charged slowly over 30 minutes. Vigorous gas evolution wasnoted during the addition. The reaction was monitored by HPLC and deemedcomplete after 1.5 h. The reaction mixture was cooled to ambienttemperature, treated with 10% aqueous citric acid (250 mL), extractedwith MTBE (2×500 mL), dried, and concentrated to afford the product(31.99 g, 99.3%, 88.1% AUC by HPLC). This reaction was repeated withslight modification as described above (reducing the amount of THF usedto dissolve the acetophenone to 3 mL/g from 10.7 mL/g with improvedcontrol of gas evolution) on a 100 g scale to give 137.1 g, >100%yield). The two lots were combined and purified by column chromatographyusing silica-gel (1 kg), eluted with 10% ethyl acetate: 90% heptane toafford the title product (105 g, 75% yield) as a pale yellow color oil.Impure fractions were collected and provided 22.8 g (16.3% yield) of theproduct.

Description 2 2-Amino-1-(4-(octyloxy)-3-(trifluoromethyl)phenyl)ethanonehydrochloride (D2)

To a solution of 1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (D1)(0.5 g, 1.0 equivalent) in CH₂Cl₂/MeOH (4:1, 10 mL) was added Bu₄NBr₃(0.76 g, 1.0 equiv). The reaction mixture was stirred at roomtemperature for 3 hours. TLC (4:1, Hex/EtOAc), R_(f)=0.6. The solventwas removed in vacuo, and re-dissolved in DMF (10 mL). NaN₃ (0.31 g, 3.0equiv) was added to the reaction and the resulting mixture was thenstirred at room temperature for 2 hrs. The solvent was removed in vacuoand the product was purified by silica gel column chromatography usingthe Combi-Flash system (Hex:EtOAc) to give the azido-acetophenoneproduct. TLC (4:1, Hex/EtOAc), R_(f)=0.4. The residue was then dissolvedin concentrated HCl (1.0 mL) and MeOH (20 mL). 10% Pd/C (100 mg) wasadded and the mixture stirred under an atmosphere of H₂ (g) for 3 hours.The reaction mixture was then filtered and evaporated to dryness to givethe title product as a yellow solid 98% (570 mg yield). TLC (4:1,Hex/EtOAc), R_(f)=0.6.

Description 2 Alternative Method (D2A)2-Amino-1-(4-(octyloxy)-3-(trifluoromethyl)phenyl)ethanone hydrochloride(D2)

A 5 L round bottom flask was charged with1-(4-(Octyloxy)-3-(trifluoromethyl)phenyl)ethanone (D1A) (128 g, 0.40mol), anhydrous dichloromethane (3.2 L), tetrabutylammonium tribromide(175 g, 0.36 mol, 0.9 equiv), methanol (640 mL) and stirred for 1 hourat room temperature (18 to 23° C.) and then treated with additionaltetrabutylammonium tribromide (20 g, 0.1 equiv) and held for fiveadditional hours. The reaction was deemed complete by TLC analysis (10%ethyl acetate in toluene) and concentrated to a residue. The residue waspurified by column chromatography using silica gel (2.7 kg), eluted with10% ethyl acetate: 90% heptane to afford a foamy solid (128 g, 80%yield). A 3 L round bottom flask was charged with a solution of thefoamy solid (128 g, 0.32 mol) in acetonitrile (1 L) and sodiumdiformylamide (36.9 g, 0.38 mol, 1.2 equiv), and heated to 65° C. for 2hours. The reaction was assayed by TLC and appeared to be approximately50% complete. The reaction was allowed to continue for a further 10hours, at which point was found to be complete by TLC. The mixture wascooled to room temperature (18 to 23° C.) and charged with MTBE (1 L),stirred for 15 minutes, filtered, the solids washed twice with MTBE(2×250 mL). The filtrates were combined and concentrated to thick oil.The oil was taken up in reagent alcohol (1.1 L), charged with 10 N HCl(100 mL) and heated to 70° C. and held for 3 hours, at which point TLCindicated the reaction to be complete. The mixture was cooled to 40-50°C. and transferred to a rotavap and the ethanol removed, and azeotropedthree times with toluene (3×1 L) to afford the title product (149 g,quantitative yield) as gummy oil.

Description 3(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(D3)

To a solution of the(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-2-methylpropanoic acid (5.0g, 1.0 equiv) in CH₂Cl₂/MeOH (4:1, 50 mL) at 0° C. was added a solutionof TMS-CHN₂ (2.0 M in diethyl ether or hexanes, 12.5 mL, 1.1 equiv)drop-wise until the colourless solution turned a light yellow colour.The reaction mixture was stirred for 20 minutes at 0° C. then a fewdrops of acetic acid were added to quench the last unreacted TMS-CHN₂(the solution turns colourless from light yellow). The solvent wasremoved in vacuo. TLC (2:1, Hex/EtOAc), R_(f)=0.4.

The residue was dissolved in acetone (30 mL), 2,2-dimethoxypropane (DMP)(12 mL) and BF₃.OEt₂ (2 mL). The solution was stirred at RT for 4 hours.The solvent was removed in vacuo and the product was purified by silicagel column chromatography using the Combi-Flash system (Hex:EtOAc). TLC(3:1, Hex/EtOAc), R_(f)=0.6; ¹H NMR (400 MHz, CDCl₃) δ 4.06-4.12 (m,1H), 3.73-3.83 (m, 4H), 1.55-1.64 (m, 9H), 1.48 (br s, 3H), 1.41 (br s,6H).

The purified residue was dissolved in THF (40 mL) and to the solutionwas added LiOH (1.15 g, 1.20 equiv) in H₂O (20 mL). The solution washeated at reflux for 6 hours then stirred overnight, then concentratedin vacuo to remove most of the THF. The solution was diluted with H₂O(150 mL) and washed with Et₂O (2×150 mL). The aqueous layer was cooledto 0° C. then acidified to pH2 using concentrated HCl, then extractedwith EtOAc (2×200 mL). The EtOAc layers were combined, dried (MgSO₄),filtered, and the solvent was removed in vacuo to afford the carboxylatetitle compound as a white solid in 64% yield (3.78 g). TLC (1:1EtOAc:Hex), R_(f)=0.2; ¹H NMR (400 MHz, CDCl₃) 8 (rotamers) 4.47 (br d,0.5H, J=8.8 Hz), 4.17 (br d, 0.5H, J=8.8 Hz), 3.85 (br d, 0.5H, J=8.8Hz), 3.78 (br d, 0.5H, J=8.8 Hz), 1.38-1.67 (m, 18H).

Description 3 Alternative Method (D3A)(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(D3)

A 22 L round bottom flask was inerted and charged with(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-2-methylpropanoic acid (564g, 2.57 mol), acetone (8.4 L) and stirred. The mixture was slowlycharged with 1,8-Diazabicyclo[5.4.0]undec-7-ene (770 mL, 5.1 mol, 2equiv.). The addition was exothermic and the temperature was maintainedbelow 25° C. The mixture was stirred for 45 minutes at ambientconditions, and then cautiously charged with iodomethane (320 mL, 5.1mol, 2 equiv). The addition was exothermic and the temperature wasmaintained below 25° C. The mixture was allowed to stir overnight atroom temperature (18 to 23° C.). After 16 hours, TLC indicated startingmaterial remained. The reaction was charged with iodomethane (320 mL,5.1 mol, 2 equiv), warmed to 30° C. for 4 hours, and then allowed tostir overnight at room temperature (18 to 23° C.). After 16 hours, assayby TLC indicated the reaction was complete. The reaction mixture wascombined with another reaction mixture of a scale of 275 g. The combinedreaction mixtures were concentrated under vacuum to a residue,transferred into a reactor, charged with water (8.4 L), ethyl acetate(8.4 L), mixed thoroughly, phases split, extracted aqueous phase oncemore with ethyl acetate (8.4 L), combined organic phases, washed with 5%w/v citric acid (900 mL), brine (1 L), dried with magnesium sulfate,filtered over Celite, and concentrated to afford an oil (925 g, 104%yield). A 22 L round bottom flask was charged with this crude product(925 g, 3.8 mol based on theoretical output from previous step),dichloromethane (10 L), 2,2-Dimethoxypropane (2.6 L), and mixed. Borontrifluoride diethyl etherate (200 mL, 1.62 mol, 0.42 equiv) indichloromethane (1.2 L) was cautiously charged over 45 minutes. Theresulting dark solution was stirred over night at room temperature (18to 23° C.). After 16 hours TLC indicated the reaction was complete. Themixture was slowly quenched with saturated sodium bicarbonate (3.5 L)while maintaining the temperature below 25° C. Once the quench wascomplete, the mixture was stirred for 30 minutes, the phases separated,and the aqueous extracted with dichloromethane (3.5 L), the organicphases were combined, washed with saturated sodium bicarbonate (3 L),concentrated to obtain compound a yellow oil (1070 g, quantitative). A22 L round bottom flask was charge with lithium hydroxide monohydrate(482 g, 11.4 mol, 3 equiv), water (2.3 L), methanol (2.1 L), a solutionof crude yellow oil (1046 g—based on theoretical output of previousstep, 3.82 mol) in tetrahydrofuran (6.5 L). The mixture was stirred for72 hours at room temperature (18 to 23° C.). TLC indicated the reactionwas complete. The mixture was concentrated under vacuum at 40° C., theresidue was charged with water (10 L), MTBE (6 L), mixed thoroughly, andthe phases split. The organic phase was washed with water (4 L), theaqueous phases were combined, and solid citric acid was charged inportions until a pH of 3 was obtained. The aqueous was extracted withethyl acetate (2×10 L), ethyl acetate phases were combined, washed withbrine (7 L), dried with magnesium sulfate, filtered over Celite, andconcentrated to afford the title product (770 g, 77.6% yield) as an offwhite solid.

Description 4 (R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(D4)

To a solution of(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(D3) (100 mg, 1 equiv), HATU (220 mg, 1.5 equiv), and DIEA (0.67 mL, 10equiv) in DCM (5 mL) was added2-amino-1-(4-(octyloxy)-3-(trifluoromethyl)phenyl)ethanone hydrochloride(D2) (142 mg, 1.0 equivalents). The solvent removed in vacuo and theproduct was purified with silica gel column chromatography using theCombi-Flash system (Hex:EtOAc). This resulted in a colourless, thick oilwhich was dissolved in toluene (5 mL) with Lawesson's reagent (280 mg, 3equiv). The resultant mixture was heated at 120° C. for 2 hours toproduce the title product as a colourless oil 41% yield (90 mg). TLC(1:2 EtOAc:Hex), R_(f)=0.3; MS (ESI, M+Na)=572.99; ¹H NMR (400 MHz,CDCl₃) δ 8.21 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.05 (d, 1H, J=8.4 Hz),4.62-4.79 (m, 2H), 4.13 (t, 2H, J=6.4 Hz), 3.28 (br s, 1H), 1.22-1.90(m, 30H), 0.89 (t, 3H, J=6.4 Hz).

Description 4 Alternative Method (D4A) (R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(D4)

A 5 L, round bottom flask was charged with HATU (147 g, 0.38 mol, 1.2equiv), methylene chloride (600 mL), N,N-dimethylformamide (300 mL),diisopropylethylamine (83.5 g, 0.64 mol, 2 equiv) and the mixture cooledto 1-15° C. A solution of(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(D3A) (83.7 g, 0.32 mol, 1 equiv) in methylene chloride (600 mL) wascharged over a period of 30 minutes. The mixture was warmed to roomtemperature (18 to 23° C.) and stirred for 1 hour. A separate flask wascharged with solution of2-Amino-1-(4-(octyloxy)-3-(trifluoromethyl)phenyl)ethanone hydrochloride(D2A) (149 g, 0.32 mol -based on theoretical output) in methylenechloride (1 L), N,N-dimethylformamide (400 mL) and diisopropylethylamine(125 g, 0.96 mol, 3 equiv). The solution of the second flask was slowlycharged to the first flask over a period of 35 minutes. The resultingbrown solution was stirred for 1 hour, at which point TLC analysisindicated the reaction was complete. The mixture was transferred to arotavap and concentrated to remove the methylene chloride. The mixturewas transferred once more to the round bottom flask and charge with MTBE(3 L), 10% w/v aqueous sodium chloride solution (3 L), stirred for 10minutes, phases separated, and the aqueous extracted once more with MTBE(1 L). The organic phases were combined, washed twice with 10% w/vaqueous sodium chloride solution (2×1 L), dried with magnesium sulfate,and concentrated to a residue which was purified by columnchromatography using silica-gel (1.3 kg), eluted with 5% ethyl acetate:95% heptane to 30% ethyl acetate: 70% heptane to afford the product as ayellow-coloured oil (137.5 g, 74% yield). A 5 L round bottom flask wascharged with Lawesson's reagent (116.2 g, 0.28 mol, 1.2 equiv), asolution of the yellow-coloured oil (137 g, 0.239 mol) in toluene (2 L).The resulting slurry was heated to 80° C. which after 30 minutes becamea clear solution. The solution was held at 80° C. for another 2 hours,at which point TLC (25% ethyl acetate: 75% heptane) indicated thereaction was complete. The reaction mixture was cooled to roomtemperature (18 to 23° C.), charged with saturated sodium bicarbonatesolution (1 L), 10% w/v sodium chloride (1 L), ethyl acetate (1 L), andstirred for 30 minutes. The phases were separated and the aqueousextracted once more with ethyl acetate (1 L). The organic phases werecombined and concentrated to a residue. The residue was purified bycolumn chromatography using silica-gel (1.3 kg), eluted with 100%heptane to 30% ethyl acetate: 70% heptane to afford the title product(91.1 g, 67% yield, 96.6% AUC by HPLC) as a brown oil.

Description 5 4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (D5)

1-octanol (315 μL, 2.0 mmol), THF (5 mL), potassium t-butoxide (5 mL, 1Msolution in THF), 4-Fluoro-3-trifluoromethylbenzoic acid (417 mg, 2.0mmol) were mixed and heated at 75° C. for 3-4 hrs. The reaction mixturewas then diluted with ethyl acetate and washed with water. The waterlayer was acidified and extracted with ethyl acetate. The organic layerwas washed with brine and dried over Na₂SO₄ and concentrated to affordthe title compound (632 mg, HPLC purity >95%), which was used for nextreaction without further purification. HPLC retention time on a C8(2)column (30×3.00 mm, 3μ) was 3.28 min with gradient 50-98%acetonitrile-H₂O (0.1% trifluoroacetic acid (TFA)) in 3.5 min as mobilephase.

Description 5 Alternative Method A (D5A)4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (D5)

A 12 L round bottom flask was inerted and charged with 1-octanol (103 g,0.793 mol, 1 equiv), THF (2 L), 1 M potassium tert-butoxide (2 L, 2.5equiv) and heated to 65° C. and held for 45 minutes. The reaction wascharged over 1 hour with 4-fluoro-3-trifluoromethyl benzoic acid (165 g,0.793 mol) while maintaining the temperature at 64 to 67° C. After 2hours, the reaction mixture was sampled. The sample was concentrated,quenched into 1 N HCl, extracted with ethyl acetate, removed the ethylacetate, diluted with acetonitrile and injected in to the HPLC. Thereaction was complete. The reaction mixture was stirred overnight at 18to 23° C. The mixture was cooled to 5 to 10° C. and cautiously quenchedwith water (1.6 L). The quench was exothermic and the temperature wasmaintained at T<10° C. The resulting mixture was concentrated undervacuum until no noticeable THF was coming off. The resulting aqueousmixture was acidified to pH 1 to 2 using 6 N HCl (400 mL). The mixturewas extracted with MTBE (2×2.5 L). The MTBE phases were combined, washedwith brine (2 L), dried with magnesium sulfate, filtered over Celite,concentrated to afford the title product (279 g, 111% yield, 95.6% AUCby HPLC) as a tan solid.

Description 6 4-(Octyloxy)-3-(trifluoromethyl)benzohydrazide (D6)

4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (D5) (600 mg, 1 equiv) wasstirred with HATU (859 mg, 1.2 equiv) and DIEA (1.63 mL, 5 equiv) inCH₂Cl₂-DMF (10 mL, 4:1, 3 equivalents) followed by addition of hydrazine(282 μL, 3 equiv). The reaction mixture was then diluted with ethylacetate and washed with water and brine. The organic layer was driedover Na₂SO₄ and concentrated in vacuo to afford the title compound (661mg). MS (ESI): 333.08 (MH⁺)

Another batch was also made using D5 (32 mg, 1 equivalent), HATU (46 mg,1.2 equivalents), DIEA (87 μL, 5 equiv) in CH₂Cl₂-DMF (1.5 mL, 2:1)followed by addition of hydrazine (1.5 μL, 3 equiv).

Description 6 Alternative Method (D6A)4-(Octyloxy)-3-(trifluoromethyl)benzohydrazide (D6)

A 5 L 3 neck, round bottom flask was inerted and charged with CDI (153g, 0.94 mol, 1.2 equiv), 4-(Octyloxy)-3-(trifluoromethyl)benzoic acid(D5A) (250 g based on theoretical output of previous step, 0.78 mol),THF (2.5 L) and stirred at 18 to 23° C. for 1 hour. A separate 12 Lround bottom flask was inerted and charged with hydrazine monohydrate(235 g, 4.71 mol, 6 equiv) and THF (1.2 L). The contents of the firstflask was charged to the second flask over 1 hour. During the addition,the temperature was maintained at T<25° C. Once the addition wascomplete, the mixture was stirred for 2 hours at 18 to 23° C., at whichpoint TLC indicated the reaction was complete. The mixture wasconcentrated under vacuum at 35 to 40° C. until approximately 10 to 15%of the original volume was attained. Water (2 L) and brine (2 L) werecharged to the mixture which was then extracted with dichloromethane(2×2.5 L). There was a small emulsion during each extraction. Theorganic phases were combined, washed with brine (500 mL), dried withmagnesium sulfate, filtered over Celite, and concentrated to afford thetitle product (247 g, 94% yield, 96% AUC by HPLC) as a yellow solid.

Description 7(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(D7)

To a solution of the(S)-2-(tert-butoxycarbonylamino)-3-hydroxy-2-methylpropanoic acid (5.0g, 1.0 equiv) in CH₂Cl₂/MeOH (4:1, 50 mL) was added a solution ofTMS-CHN₂.

The residue was dissolved in acetone (30 mL), 2,2-dimethoxypropane (DMP)(12 mL) and BF₃.OEt₂ (2 mL). The solution was stirred at RT for 4 hours.The solvent was removed in vacuo and the product was purified by silicagel column chromatography using the Isco system (0-30% Hex:EtOAc) togive the oxazoline methyl ester intermediate.

The purified residue was dissolved in H₂O-THF (1:4) and to the solutionwas added LiOH (1.16 g). The solution was heated at refluxed forovernight, cooled to room temperature and condensed to remove the THF.The aqueous material was diluted with H₂O (˜100 mL), acidified to pH2with 10% KHSO₄ and then extracted with EtOAc. The Eorganic layers weredried over Na₂SO₄, and condensed to afford the title compound in 66%yield (3.29 g).

Description 8 (S)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(D8)

(R)-3-(tert-Butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylic acid(D7) (210 mg, 0.81 mmol), HATU (372 mg, 0.98 mmol), diisopropylethylamine (DIEA) (0.705 mL, 4.1 mmol), CH₂Cl₂-DMP and4-(octyloxy)-3-(trifluoromethyl)benzohydrazide (D6) (270 mg, 0.81 mmol)were mixed together. The reaction was condensed, diluted with ethylacetate, washed with water and brine, and condensed again. Another batchwas made using this method with (D7) (0.1 mmol), HATU (46 mg, 0.12mmol), DIEA (87 μL, 0.5 mmol), CH₂Cl₂-DMF and4-(octyloxy)-3-(trifluoromethyl)benzohydrazide (D6) (>6 mg, 0.1 mmol).The batches were chromatographed and combined to provide the titleproduct (428 mg). MS (ESI): 573.84 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ 9.43(br, 2H), 8.06 (d, 1H, J=2.0 Hz), 7.94 (dd, 1H, J=8.8 Hz, J=2.0 Hz),6.96 (d, 1H, J=8.8 Hz), 4.52 (br, 1H), 4.07 (t, 2H, J=6.4 Hz), 3.76 (br,1H), 1.82 (m, 2H), 1.67 (s, 6H), 1.57 (s, 3H), 1.51 (s, 9H), 1.51-1.43(m, 4H), 1.38-1.24 (m, 6H), 0.88 (t, 3H, J=7.2 Hz).

Description 8 Alternative Method (D8A) (S)-tert-Butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(D8)

A 5 L round bottom flask was inerted and charged with HATU (199 g, 0.52mol, 1.2 equiv), N,N-dimethylformamide (380 mL), and mixed. A solutionof (R)-3-(tert-butoxycarbonyl)-2,2,4-trimethyloxazolidine-4-carboxylicacid (D3A) (133.1 g, 0.43 mol, 1 equiv), dichloromethane (870 mL), andN,N-diisopropylethylamine (155 mL, 0.88 mol, 2 equiv) was charged to theflask over 15 minutes. The resulting mixture was stirred at 18 to 23° C.for 1 hour. A solution of benzohydrazide (D6) (145 g, 0.43 mol, 1 equiv)in dichloromethane (1120 mL), and N,N-Dimethylformamide (420 mL) wascharged over 15 minutes then stirred at 18 to 23° C. for 1 hour. After 1hour, TLC indicated the reaction was complete. The mixture wasconcentrated, partitioned between ethyl acetate (2.5 L) and water (2.5L). The phases were split and the aqueous extracted once more with ethylacetate (1 L). The organic phases were combined, washed with 10% w/vsodium chloride (2×1 L), dried with magnesium sulfate, filtered overCelite, and concentrated under vacuum to afford the crude product (367g, 146% yield). The crude material was purified using a silica-gelcolumn (2 kg) which was eluted with 5 to 25% ethyl acetate in heptane togive the title product (270 g, 108% yield, 95.9% AUC by HPLC) as ayellow oil.

Description 9 (R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(D9)

A solution of (S)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate(D8) (228 mg, 0.39 mmol) in toluene (5 mL) was treated with Lawesson'sreagent (321 mg, 0.79 mmol). The reaction was chromatographed on asilica gel column eluted with ethyl acetate-hexane to afford the titlecompound (˜156 mg). MS (ESI): 572.17 (MH⁺), ¹H NMR (400 MHz, CDCl₃) δ8.10 (d, 1H, J=8.8 Hz), 8.08 (d, 1H, J=6.8 Hz), 7.06 (d, 1H, J=8.0 Hz),4.41 (d, 1H, J=8.0 Hz), 4.18 (d, 1H, J=9.6 Hz), 4.13-4.07 (m, 3H), 2.00(s, 3H), 1.85 (m, 2H), 1.78 (s, 3H), 1.68 (m, 4H), 1.51 (s, 3H), 1.47(m, 2H), 1.39-1.28 (m, 13H), 0.89 (t, 3H, J=7.2 Hz).

Description 9 Alternative Method (D9A) (R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(D9)

A 12 L, round bottom flask was inerted and charged with Lawesson'sreagent (211.5 g, 0.52 mol, 1.2 equiv), a solution of (s)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)benzoyl)-hydrazinecarbonyl)oxazolidine-3-carboxylate(D8A) (250 g -based on theoretical output, 0.43 mol) in toluene (2.5 L),and the resulting slurry was heated to 80° C. and held for 3 hours. TLCindicated the reaction was complete. The mixture was cooled to 18-23°C., charged with saturated NaHCO₃ solution (2 L), which was slightlyexothermic. The aqueous was extracted twice with ethyl acetate (2 L, 1.5L), the organic phases were combined, concentrated, dissolved indichloromethane (500 mL), charged with silica-gel (500 g), concentratedto remove dichloromethane, and purified using a silica-gel (2.5 kg)column which was eluted with 5% ethyl acetate: 95% heptane to afford thetitle product (185 g, 74% yield, 95% AUC by HPLC) as a yellow color oil.

Example 1(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol(E1)

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(D4) (90 mg, 1 equiv) and para toluenesulfonic acid (PTSA, 300 mg, 10equiv) in MeOH (6 mL) was refluxed for 4 hours. The solvent was removedfrom ⅔ of the reaction mixture and the product was purified bypreparative HPLC to give the title product as the trifluoroacetate salt(35 mg). MS (ESI, M+H⁺)=431.01; ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s,1H), 7.88 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 7.85 (d, 1H, J=2.4 Hz), 7.34 (d,1H, J=8.4 Hz), 5.77 (br s, 1H), 4.14 (t, 2H, J=6.4 Hz), 3.76 (dd, 1H,J=11.2, Hz, J=1.2 Hz), 3.66 (dd, 1H, J=11.2 Hz, J=1.2 Hz), 1.73 (q, 2H,J=6.8 Hz), 1.58 (s, 3H), 1.36-1.48 (m, 2H), 1.20-1.36 (m, 8H), 0.85 (t,3H, J=6.4 Hz).

Example 1 Alternative method (E1A)(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol(E1)

(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate(47 g, 82.35 mmol), was reacted with p-TSA (2 equiv) in methanol (470mL) at reflux for 4 h at which point HPLC indicated the reaction wascomplete. The mixture was cooled to rt, concentrated to a residue, andtriturated with IPAc (235 mL). The resulting solid was filtered, washedwith IPAc (470 mL) to afford PPI-5325 p-TSA salt (45 g) as a whitesolid. The solid was converted to freebase by treating with 6 N NaOH andDCM as a solvent.

To form a hydrochloride salt of E1, the freebase (30 g, 69.84 mmol) wastaken up in 4 M HCl in dioxane (70 mL) and stirred at rt for 0.25 hours.The 1,4-dioxane was concentrated to dryness and the crude was trituratedwith acetonitrile (200 mL). The resulting mixture was stirred for 1 hand filtered the white solid (23.3 g, 60%, ¹H-NMR was consistent withstructure).

Example 2(S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyldihydrogen phosphate (E2)

E1 (25 mg, 1.0 equiv), DCM (5 mL), diethyl chlorophosphate (85 μL, 10.0equiv) and triethylamine (165 μL, 20.0 equiv) were stirred overnight.The obtained phospho-diester intermediate was reacted with excessbromotrimethylsilane in DCM for 5 hrs. The resulting phosphate waspurified by preparative HPLC as the trifluoroacetate salt (10 mg). MS(ESI, M+H⁺)=511.1.

Example 3(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(E3)

A solution of (S)-tert-butyl2,2,4-trimethyl-4-(2-(4-(octyloxy)-3-(trifluoromethyl)-benzoyl)hydrazinecarbonyl)oxazolidine-3-carboxylate(D9) (156 mg, 0.27 mmol) in methanol (10 mL) was treated withp-toluenesulfonic acid monohydrate (259 mg, 1.36 mmol) at 70° C. for 3hours. Two thirds of the reaction mixture was then purified by prep HPLCon a C8(2) column ((Luna, 5μ, 100×21.10 mm) with acetonitrile-H₂O (0.1%TFA) as mobile phase and gradient 30-98% in 20 min. The title compoundwas obtained as the bis-TFA salt (24 mg). MS (ESI): 432.00 (MH⁺); ¹H NMR(400 MHz, DMSO-d₆) δ 8.21 (dd, 1H, J=2.0 Hz, J=8.8 Hz), 8.15 (d, 1H,J=2.0 Hz), 8.09 (br s, 2H), 7.45 (d, 1H, J=8.8 Hz), 5.96 (t, 1H, J=4.8Hz), 4.21 (t, 2H, J=6.4 Hz), 3.81 (dd, 1H, J=11.2 Hz, J=5.2 Hz), 3.73(dd, 1H, J=11.2 Hz, J=5.2 Hz), 1.76 (m, 2H), 1.66 (s, 3H), 1.44 (m, 2H),1.28 (m, 8H), 0.86 (t, 3H, J=6.8 Hz).

The remaining third of the reaction was condensed and the residuere-dissolved in ethyl acetate and washed with aqueous NaHCO₃, brine,dried over brine and condensed again to provide crude product for use inExample 4.

Example 3 Alternative Method (E3A)(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol(E3)

A 5 L round bottom flask was inerted and charged with p-toluene sulfonicacid monohydrate (209 g, 1.09 mol, 5 equiv) and a solution of(R)-tert-Butyl2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate(125 g, 0.22 mol) in methanol (2.5 L), and heated to reflux. After 1.5 hHPLC indicated reaction complete. The heat was turned off and themixture was allowed to cool to room temperature (18 to 23° C.) andstirred for 12 hours. The mixture was concentrated under vacuum to aresidue to provide the title product. The residue was taken up indioxane (2 L), charged with 4 M HCl in dioxane (820 mL, 3.28 mol, 15equiv), heated to 50° C. for 45 minutes, cooled to 18-23° C., stirredfor 2 hours, filtered over a glass flitted filter, displaced once withMTBE (300 mL), slurried once with MTBE (300 mL), and dried on the filterto afford a hydrochloride of E3 (72 g, solvent wet).

Three batches of the hydrochloride of E3 synthesised using this methodwere combined (totaling 143 g, solvent wet), slurried twice in MTBE (750mL, 500 mL), the solvent was filtered off each time, the material wastransferred to a vacuum oven and dried overnight at room temperature (18to 23° C.). ¹H-NMR indicated the presence of dioxane (0.24% by weight).Further drying at an increased temperature of 30 to 35° C. for 72 hoursafforded a hydrochloride (135 g, 98.6% AUC by HPLC) as a white solid.

Example 4(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate (E4)

Crude product from E3 (30 mg, 0.069 mmol) was added todiethylchlorophosphate (10 μL, 0.69 mmol) and triethylamine (194 μL,1.39 mmol,) in DCM and stirred for approx 36 hrs. The reaction mixturewas then condensed and treated with bromotrimethylsilan (0.3 mL) in DCM(5 mL) to provide the title compound (˜2 mg). MS (ESI): 511.98 (MH⁺),

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroalykl, —O-alkyl, —O-aryl, —O-heteroaryl, —S-alkyl,alkylene-O-alkyl, alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂,alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino,alkylene-CO-dialkylamino, alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl—CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂, —CO-alkylamino,—CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which maybe optionally substituted on carbon with 1, 2, or 3 groups selected fromhalo, alkyl, haloalkyl, —CF₃, aryl, —CN, —OH, or —O-alkyl; A is(C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, each ofwhich may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl; R′ and R″ are eachindependently hydrogen, halogen, alkyl optionally substituted on carbonwith halogen, alkyl, or taken together with the carbon to which they areattached form C═O or a 3, 4, 5, or 6-membered ring, optionallycontaining 1 or 2 heteroatoms selected from ONH, N-alkyl, SO, or SO₂,any of which may be optionally substituted on carbon with alkyl orhalogen R₂ is cyano, alkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl; R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl,—O-alkyl, —O-aryl, —O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl,alkylene-O-alkyl, alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂,alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino,alkylene-CO-dialkylamino, alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl—CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂, —CO-alkylamino,—CO-dialkylamino, amino, alkylamino, and dialkylamino, any of which maybe optionally substituted on carbon with 1, 2, or 3 groups selected fromhalo, alkyl, OH, or —O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H; R₅ and R₆ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkylene-OH, aryl,alkylene-O-alkyl, —CO₂H, CO₂-alkyl, alkylene-OC(O)alkyl, cycloalkyl,heterocyclo, —C(O)-alkyl, —C(O)-aryl, C(O)-aralkyl, —C(O)—Oalkyl,—C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino, alkylene-alkylamino, andalkylene-dialkylamino, any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, CO₂H, CO₂alkyl or alkoxy; or R₅and R₆, together with the nitrogen to which they are attached, may forma 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy; R₇ is selected from the group consisting of —OH,—O-alkyl, alkylene-OH, —CO₂H, alkylene-CO₂H, —C(O)O-alkyl,-alkylene-CO₂-alkyl, —C(O)O-aryl, —CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl,—CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2), —OPO₃R_(p1)R_(p2),—CH₂PO₃R_(p1)R_(p2), —OPO₂(S) R_(p1)R_(p2), and—C(Z′)(Z″)PO₃R_(p1)R_(p2), any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein Z′is hydroxyl or halogen; Z″ is H or halogen; R_(p1) and R_(p2) are eachindependently hydrogen, C₁-C₆-alkyl, aryl, or one of the followinggroups:

and Y is heterocyclo or heteroaryl.
 2. A compound of claim 1, wherein R2is alkyl substituted with 1, 2 or 3 halo groups.
 3. A compound of claim1, wherein R2 is trifluoromethyl.
 4. A compound of formula II

or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroalykl, —O-alkyl, —O-aryl, —O-heteroaryl, —S-alkyl,alkylene-O-alkyl, alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂,alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino,alkylene-CO-dialkylamino, alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl—CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂, —CO-alkylamino,—CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which maybe optionally substituted on carbon with 1, 2, or 3 groups selected fromhalo, alkyl, haloalkyl, —CF₃, —CN, —OH, or —O-alkyl; A is(C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, each ofwhich may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl; R′ and R″ are eachindependently hydrogen, halogen, alkyl optionally substituted on carbonwith halogen, alkyl, or taken together with the carbon to which they areattached form C═O or a 3, 4, 5, or 6-membered ring, optionallycontaining 1 or 2 heteroatoms selected from ONH, N-alkyl, SO, or SO₂,any of which may be optionally substituted on carbon with alkyl orhalogen R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H; R₅ and R₆ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkylene-OH, aryl,alkylene-O-alkyl, —CO₂H, CO₂-alkyl, alkylene-OC(O)alkyl, cycloalkyl,heterocyclo, —C(O)-alkyl, —C(O)-aryl, C(O)-aralkyl, —C(O)—Oalkyl,—C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino, alkylene-alkylamino, andalkylene-dialkylamino, any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, CO₂H, CO₂alkyl or alkoxy; or R₅and R₆, together with the nitrogen to which they are attached, may forma 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy; R₇ is selected from the group consisting of —OH,—O-alkyl, -alkylene-OH, —CO₂H, -alkylene-CO₂H, —C(O)O-alkyl,-alkylene-CO₂-alkyl, —C(O)O-aryl, —CH₂═CHCO₂H, —CH₂═CHC(O)O-alkyl,—CH₂═CHC(O)O-aryl, —OPO₂R_(p1)R_(p2), —OPO₃R_(p1)R_(p2),—CH₂PO₃R_(p1)R_(p2), —OPO₂(S) R_(p1)R_(p2), and—C(Z′)(Z″)PO₃R_(p1)R_(p2), any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, carboxy, or alkoxy; and wherein Z′is hydroxyl or halogen; Z″ is H or halogen; R_(p1) and R_(p2) are eachindependently hydrogen, C₁-C₆-alkyl, aryl, or one of the followinggroups:

and Y is heterocyclo or heteroaryl.
 5. A compound of formula III

or a pharmaceutically acceptable salt thereof, wherein: R₁ is hydrogen,halogen, cyano, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,aralkyl, heteroalykl, —O-alkyl, —O-aryl, —O-heteroaryl, —S-alkyl,alkylene-O-alkyl, alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂,alkylenesulfonyl, alkylene-CO-amino, alkylene-CO-alkylamino,alkylene-CO-dialkylamino, alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl—CO₂alkyl, —OH, —C(O)-alkyl, —C(O)O-alkyl, —CONH₂, —CO-alkylamino,—CO-dialkylamino, amino, alkylamino, or dialkylamino, any of which maybe optionally substituted on carbon with 1, 2, or 3 groups selected fromhalo, alkyl, haloalkyl, —CF₃, —CN, —OH, or —O-alkyl; A is(C₁-C₂₀)alkylene, (C₂-C₂₀)alkenylene, or (C₂-C₂₀)alkynylene, each ofwhich may be optionally substituted on carbon with 1, 2, or 3 groupsselected from OH, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H;X₁ is a bond or is CH₂, O, —CH₂O—, S, —S(O), —S(O)₂, —C(O)—, —C(O)O—, orNR_(x), wherein R_(x) is H or (C₁-C₆)alkyl; R′ and R″ are eachindependently hydrogen, halogen, alkyl optionally substituted on carbonwith halogen, alkyl, or taken together with the carbon to which they areattached form C═O or a 3, 4, 5, or 6-membered ring, optionallycontaining 1 or 2 heteroatoms selected from ONH, N-alkyl, SO, or SO₂,any of which may be optionally substituted on carbon with alkyl orhalogen R₃ is absent, hydrogen, halogen, cyano, alkyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, aralkyl, heteroalykl, —O-alkyl, —O-aryl,—O-heteroaryl, aralkoxy, heteroaralkoxy, —S-alkyl, alkylene-O-alkyl,alkylene-CO₂H, alkylene-CO₂alkyl, alkylSO₂, alkylenesulfonyl,alkylene-CO-amino, alkylene-CO-alkylamino, alkylene-CO-dialkylamino,alkylene-NH—CO₂H, alkylene-NH—CO₂alkyl —CO₂alkyl, —OH, —C(O)-alkyl,—C(O)O-alkyl, —CONH₂, —CO-alkylamino, —CO-dialkylamino, amino,alkylamino, and dialkylamino, any of which may be optionally substitutedon carbon with 1, 2, or 3 groups selected from halo, alkyl, OH, or—O-alkyl;

is phenyl or pyridyl;

is aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which may beoptionally substituted on carbon with 1, 2, or 3 groups selected formhalogen, alkyl, O-alkyl, CO₂H, CO₂alkyl, halogen, amino, alkylamino,dialkylamino, —O-alkyl, alkylene-O-alkyl, alkylene-OH, or alkylene-CO₂H,provided that

R₄ is hydrogen, cyano, alkyl, aryl, heteroaryl, alkylene-O-alkyl,alkylene-OH, aryl, alkylene-O-alkyl, —CO₂H, —CO₂-alkyl, alkylene-CO₂H,or alkylene-CO₂-alkyl, alkylene-OC(O)R wherein R is hydrogen or alkyl;cycloalkyl, heterocycloalkyl, alkylene-NH₂, alkylene-alkylamino, oralkylene-dialkylamino, any of which may be optionally substituted oncarbon with 1, 2, or 3 groups selected from OH, CO₂H, CO₂alkyl, halogen,amino, alkylamino, dialkylamino, —O-alkyl, alkylene-O-alkyl,alkylene-OH, or alkylene-CO₂H; R₅ and R₆ are each independently selectedfrom the group consisting of hydrogen, alkyl, alkylene-OH, aryl,alkylene-O-alkyl, —CO₂H, CO₂-alkyl, alkylene-OC(O)alkyl, cycloalkyl,heterocyclo, —C(O)-alkyl, —C(O)-aryl, C(O)-aralkyl, —C(O)—Oalkyl,—C(O)—Oaryl, —C(O)—Oaralkyl, alkylene-amino, alkylene-alkylamino, andalkylene-dialkylamino, any of which may be optionally substituted oncarbon with halogen, alkyl, hydroxyl, CO₂H, CO₂alkyl or alkoxy; or R₅and R₆, together with the nitrogen to which they are attached, may forma 3, 4, 5, or 6-membered saturated or unsaturated ring, optionallycontaining 1 or 2 additional heteroatoms selected from O, S, NH, orN-alkyl, and optionally substituted on carbon with halogen, alkyl,hydroxyl, or alkoxy; R₈ is hydrogen, alkyl or aryl; and n is 0, 1, or 2.6. A compound selected from the group consisting of:(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol;2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propane-1,3-diol;(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(5-phenylpentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-phenylbutoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(nonyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(decyloxy)-3(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazole-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(3-(trifluoromethyl)phenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(5-(4-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(5-(3-fluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-((4-phenyl-5-(trifluoromethyl)thiophen-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(7-phenylheptyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(2-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(trifluoromethyl)phenethoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-phenethoxy-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(3-phenylpropoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(benzofuran-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(benzo[b]thiophen-2-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(benzo[d][1,3]dioxol-5-ylmethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(3-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(4-(4-(trifluoromethyl)phenyl)butoxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(2S)-2-Amino-2-(5-(4-(3,7-dimethyloctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-propylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-butylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-ethylphenethoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(7,7,8,8,8-pentafluorooctyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-(2-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-(3-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(4-(4-fluorophenyl)butoxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(6-(2-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-4,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(6-(3-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(6-(4-fluorophenyl)hexyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(5-(3,4-difluorophenyl)pentyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(2,4,5-trifluorophenyl)pentyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(3-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(6-(4-(trifluoromethyl)phenyl)hexyloxy)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(octylthio)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(octylsulfonyl)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)propan-1-ol;(R)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)propan-1-ol;(S)-2-Amino-2-(3-(4-(octyloxy)-3-(trifluoromethyl)phenyl)isoxazol-5-yl)propan-m-ol;(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-ol;(S)-2-Amino-2-(5-(3-(trifluoromethyl)-4-(5-(4-(trifluoromethyl)phenyl)pentyloxy)phenyl)thiazol-2-yl)propan-1-ol; and pharmaceutically acceptable salts,phosphate derivatives, phosphate mimics, and phosphate precursor analogsthereof.
 7. The compound of claim 6 which is(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propan-1-olor a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or phosphate precursor analog thereof.
 8. The compound of claim 6which is(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)propyldihydrogen phosphate or a pharmaceutically acceptable salt thereof. 9.The compound of claim 6 which is(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-olor a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or a phosphate precursor analog thereof.
 10. The compound ofclaim 6 which is(S)-2-Amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propyldihydrogen phosphate or a pharmaceutically acceptable salt thereof. 11.The compound as defined in claim 1, 4, 5 or 6 or a pharmaceuticallyacceptable salt, phosphate derivative, phosphate mimic, or phosphateprecursor analog thereof for use as a therapeutic substance.
 12. Thecompound as defined in claim 1, 4, 5 or 6 or a pharmaceuticallyacceptable salt, phosphate derivative, phosphate mimic, or phosphateprecursor analog thereof for use in the treatment of a sphingosineassociated disorder.
 13. The compound as defined in claim 1, 4, 5 or 6or a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or phosphate precursor analog thereof for use in the treatment ofmultiple sclerosis.
 14. (canceled)
 15. (canceled)
 16. A method oftreating a sphingosine 1-phosphate associated disorder comprisingadministering to a subject a therapeutically effective amount of acompound as defined in claim 1, 4, 5 or 6 or a pharmaceuticallyacceptable salt, phosphate derivative, phosphate mimic, or phosphateprecursor analog thereof, such that the sphingosine 1-phosphateassociated disorder is treated.
 17. A pharmaceutical compositioncomprising a compound as defined in claim 1 or a pharmaceuticallyacceptable salt, phosphate derivative, phosphate mimic, or phosphateprecursor analog thereof.
 18. A process for the preparation of apharmaceutical composition according to claim
 17. 19. A process for thepreparation of a compound as defined in claim 1 or a pharmaceuticallyacceptable salt, phosphate derivative, phosphate mimic, or phosphateprecursor analog thereof.
 20. A pharmaceutical composition comprising acompound as defined in claim 4 or a pharmaceutically acceptable salt,phosphate derivative, phosphate mimic, or phosphate precursor analogthereof.
 21. A pharmaceutical composition comprising a compound asdefined in claim 5 or a pharmaceutically acceptable salt, phosphatederivative, phosphate mimic, or phosphate precursor analog thereof. 22.A pharmaceutical composition comprising a compound as defined in claim 6or a pharmaceutically acceptable salt, phosphate derivative, phosphatemimic, or phosphate precursor analog thereof.
 23. A process for thepreparation of a pharmaceutical composition according to claim
 20. 24. Aprocess for the preparation of a pharmaceutical composition according toclaim
 21. 25. A process for the preparation of a pharmaceuticalcomposition according to claim 22.